1
|
Matejcic M, Teer JK, Hoehn HJ, Diaz DB, Shankar K, Gong J, Nguyen NT, Loroña NC, Coppola D, Fulmer CG, Saglam O, Jiang K, Cress WD, Muñoz-Antonia T, Flores I, Gordián ER, Oliveras Torres JA, Felder SI, Sanchez J, Fleming JB, Siegel EM, Freedman JA, Dutil J, Stern MC, Fridley BL, Figueiredo JC, Schmit SL. Colorectal Tumors in Diverse Patient Populations Feature a Spectrum of Somatic Mutational Profiles. Cancer Res 2025; 85:1928-1944. [PMID: 40126181 DOI: 10.1158/0008-5472.can-24-0747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 08/21/2024] [Accepted: 02/25/2025] [Indexed: 03/25/2025]
Abstract
Admixed populations, including the Hispanic/Latino/a community, are underrepresented in cancer genetic/genomic studies. Leveraging the Latino Colorectal Cancer Consortium (LC3) and other existing datasets, we analyzed whole-exome sequencing data on tumor/normal pairs from 718 individuals with colorectal cancer to map somatic mutational features by ethnicity and genetic similarity. Global proportions of African, Asian, European, and Native American genetic ancestries were estimated using ADMIXTURE. Associations between these proportions and somatic mutational features were examined using logistic regression. APC, TP53, and KRAS were the top three mutated genes across all participants and in the subset of Latino individuals in LC3. In analyses examining recurrently mutated genes, tumors from patients of Latino ethnicity had fewer KRAS and PIK3CA mutations compared with tumors from non-Latino patients. Genetic ancestry overall was associated with CDC27 mutation status, and African genetic ancestry was associated with SMAD2 mutation status. In exome-wide analyses, African genetic ancestry was significantly associated with higher odds of mutation in KNCN and TMEM184B. Native American genetic ancestry was associated with a lower frequency of microsatellite instability-high tumors. The SBS11 mutational signature was associated with Native American genetic ancestry as well as Latino ethnicity. In an independent replication dataset, MSK-IMPACT, estimates of association were largely consistent in direction but nonsignificant. A meta-analysis of LC3 and MSK-IMPACT showed that African genetic ancestry was significantly associated with KRAS mutation status and MSI status. This work facilitates precision medicine initiatives by providing insights into the contribution of genetic ancestry to molecular features of colorectal tumors. Significance: Analysis of tumors from various populations can broadly characterize genomic landscapes and enhance precision medicine strategies.
Collapse
Affiliation(s)
- Marco Matejcic
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jamie K Teer
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Hannah J Hoehn
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Non-Therapeutic Research Office, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Diana B Diaz
- Non-Therapeutic Research Office, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Kritika Shankar
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio
| | - Jun Gong
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Nathalie T Nguyen
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Nicole C Loroña
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Domenico Coppola
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Clifton G Fulmer
- Department of Pathology, Robert J. Tomsich Pathology and Laboratory Medicine Institute, Cleveland Clinic Foundation, Cleveland, Ohio
| | - Ozlen Saglam
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Kun Jiang
- Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - W Douglas Cress
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Teresita Muñoz-Antonia
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Idhaliz Flores
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico
| | - Edna R Gordián
- Department of Molecular Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - José A Oliveras Torres
- Department of Basic Sciences, Ponce Research Institute, Ponce Health Sciences University, Ponce, Puerto Rico
| | - Seth I Felder
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Julian Sanchez
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jason B Fleming
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Erin M Siegel
- Department of Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Non-Therapeutic Research Office, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
- Department of Gastrointestinal Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jennifer A Freedman
- Division of Medical Oncology, Department of Medicine, Duke University School of Medicine, Durham, North Carolina
- Duke Cancer Institute, Durham, North Carolina
| | - Julie Dutil
- Division of Clinical and Translational Cancer Research, Comprehensive Cancer Center of the University of Puerto Rico, San Juan, Puerto Rico
| | - Mariana C Stern
- Department of Population and Public Health Sciences, Keck School of Medicine, University of Southern California/Norris Comprehensive Cancer Center, Los Angeles, California
| | - Brooke L Fridley
- Department of Biostatistics and Bioinformatics, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida
| | - Jane C Figueiredo
- Department of Medicine, Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, California
| | - Stephanie L Schmit
- Genomic Medicine Institute, Cleveland Clinic, Cleveland, Ohio
- Department of Molecular Medicine, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University School of Medicine, Cleveland, Ohio
| |
Collapse
|
2
|
Kim M, Gu W, Iwakawa RK, Kina S, Nakajima T, Higuchi T, Ogawa M, Suzuki K, Tsushima Y, Yokoo S. Integrative Analysis of 18F-FDG PET Radiomics and mRNA Expression in Recurrent/Metastatic Oral Squamous Cell Carcinoma: A Cross-Sectional Study. Mol Imaging Biol 2025:10.1007/s11307-025-02012-5. [PMID: 40369386 DOI: 10.1007/s11307-025-02012-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2024] [Revised: 03/25/2025] [Accepted: 04/17/2025] [Indexed: 05/16/2025]
Abstract
BACKGROUND This study explored the relationship between mRNA expression profiles obtained through next-generation sequencing (NGS) and 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) texture analysis in patients with treatment-resistant oral squamous cell carcinoma (OSCC) who were treated with molecular-targeted drugs. We analyzed the correlation between 18F-FDG PET texture features and NGS data in a small cohort of five patients with recurrent or metastatic OSCC who received molecular-targeted drugs after surgery. Patients were categorized into two groups based on treatment response: responders (n = 3) and non-responders (n = 2). To validate our findings, we examined transcriptomic data from 292 OSCC patients in The Cancer Genome Atlas (TCGA) database. RESULTS The gene ankyrin repeat and SOCS box containing two (ASB2) was significantly overexpressed in non-responders and strongly correlated with specific PET radiomic features, including GLRLM_GLNU, GLRLM_RLNU, and GLZLM_GLNU (p < 0.05). High ASB2 expression was also associated with poor prognosis in OSCC patients (p < 0.05) and decreased overall survival, as shown by Kaplan-Meier analysis of the TCGA database (p = 0.017). CONCLUSIONS Integrating ASB2 expression data with 18F-FDG PET texture features could potentially improve the prediction of treatment outcomes in treatment-resistant OSCC patients undergoing molecular-targeted therapy.
Collapse
Affiliation(s)
- Mai Kim
- Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Wenchao Gu
- Department of Artificial Intelligence Medicine, Graduate School of Medicine, Chiba University, Chiba, Japan.
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Tsukuba, Ibaraki, Japan.
| | - Reika Kawabata- Iwakawa
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan
| | - Shinichiro Kina
- Division of Integrated Oncology Research, Gunma University Initiative for Advanced Research (GIAR), Gunma University, Maebashi, Japan
- Department of Pharmacology, Graduate School of Medicine, University of the Ryukyus, Okinawa, Japan
| | - Takahito Nakajima
- Department of Diagnostic and Interventional Radiology, University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Tetsuya Higuchi
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Masaru Ogawa
- Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Keisuke Suzuki
- Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Yoshito Tsushima
- Department of Diagnostic Radiology and Nuclear Medicine, Gunma University Graduate School of Medicine, Maebashi, Japan
| | - Satoshi Yokoo
- Department of Oral and Maxillofacial Surgery, and Plastic Surgery, Gunma University Graduate School of Medicine, Maebashi, Japan
| |
Collapse
|
3
|
Li Y, Song C, Wang H, Di W, Chen Y, Hu Y, Li P, Chen J, Ren Y, Gong J, Wang Q. Novel prognostic biomarkers in small cell lung cancer reveal mutational signatures, genomic mutations, and immune implications. Sci Rep 2025; 15:15592. [PMID: 40320401 PMCID: PMC12050310 DOI: 10.1038/s41598-025-00222-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Accepted: 04/25/2025] [Indexed: 05/08/2025] Open
Abstract
Small cell lung cancer (SCLC) is a highly malignant lung cancer subtype with a dismal prognosis and limited treatment options. This study aimed to identify new prognostic molecular biomarkers for SCLC and explore their immune-related implications for treatment strategies. We analyzed 200 SCLC samples via whole-exome sequencing (WES) and 313 samples by targeted sequencing. A smoking-related SBS4 mutational signature was linked to poorer prognosis and lower tumor mutational burden (TMB), while the APOBEC-mediated SBS13 signature was associated with better prognosis and higher TMB. We identified a molecular subtype with the worst outcomes and lowest TMB in both cohorts. Among 38 high-frequency mutated genes associated with SCLC prognosis, only UNC13A mutations were beneficial. Patients with UNC13A mutations had favorable immune infiltration and tumor immunogenicity. Additionally, TP53 splice site mutations were related to the worst survival outcomes. In conclusion, we discovered new molecular biomarkers for SCLC prognosis. Our findings on their immunological characteristics offer insights for developing novel SCLC treatment strategies.
Collapse
Affiliation(s)
- Yuting Li
- Department of Radiation Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - Chen Song
- Department of Hematology Laboratory, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - Haijun Wang
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - Wenyu Di
- Department of Pathology, Xinxiang Key Laboratory of Precision Medicine, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - Yangyang Chen
- Department of Radiology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - Yuanyuan Hu
- Department of Radiation Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - Peiheng Li
- Department of Radiology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - Jie Chen
- Department of Radiology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China
| | - Yanfeng Ren
- Department of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Shandong Second Medical University, Baotong Xi Street, Weicheng District, Weifang, 261053, Shandong, China.
| | - Jing Gong
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, 200032, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032, China.
| | - Qinghua Wang
- Department of Radiation Oncology, The First Affiliated Hospital of Xinxiang Medical University, Xinxiang, 453100, China.
- Department of Health Statistics, Key Laboratory of Medicine and Health of Shandong Province, School of Public Health, Shandong Second Medical University, Baotong Xi Street, Weicheng District, Weifang, 261053, Shandong, China.
| |
Collapse
|
4
|
Chalepaki AM, Gkoris M, Chondrou I, Kourti M, Georgakopoulos-Soares I, Zaravinos A. A multi-omics analysis of effector and resting treg cells in pan-cancer. Comput Biol Med 2025; 189:110021. [PMID: 40088713 DOI: 10.1016/j.compbiomed.2025.110021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 02/09/2025] [Accepted: 03/11/2025] [Indexed: 03/17/2025]
Abstract
Regulatory T cells (Tregs) are critical for maintaining the stability of the immune system and facilitating tumor escape through various mechanisms. Resting T cells are involved in cell-mediated immunity and remain in a resting state until stimulated, while effector T cells promote immune responses. Here, we investigated the roles of two gene signatures, one for resting Tregs (FOXP3 and IL2RA) and another for effector Tregs (FOXP3, CTLA-4, CCR8 and TNFRSF9) in pan-cancer. Using data from The Cancer Genome Atlas (TCGA), The Cancer Proteome Atlas (TCPA) and Gene Expression Omnibus (GEO), we focused on the expression profile of the two signatures, the existence of single nucleotide variants (SNVs) and copy number variants (CNVs), methylation, infiltration of immune cells in the tumor and sensitivity to different drugs. Our analysis revealed that both signatures are differentially expressed across different cancer types, and correlate with patient survival. Furthermore, both types of Tregs influence important pathways in cancer development and progression, like apoptosis, epithelial-to-mesenchymal transition (EMT) and the DNA damage pathway. Moreover, a positive correlation was highlighted between the expression of gene markers in both resting and effector Tregs and immune cell infiltration in adrenocortical carcinoma, while mutations in both signatures correlated with enrichment of specific immune cells, mainly in skin melanoma and endometrial cancer. In addition, we reveal the existence of widespread CNVs and hypomethylation affecting both Treg signatures in most cancer types. Last, we identified a few correlations between the expression of CCR8 and TNFRSF9 and sensitivity to several drugs, including COL-3, Chlorambucil and GSK1070916, in pan-cancer. Overall, these findings highlight new evidence that both Treg signatures are crucial regulators of cancer progression, providing potential clinical outcomes for cancer therapy.
Collapse
Affiliation(s)
- Anna-Maria Chalepaki
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus.
| | - Marios Gkoris
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus.
| | - Irene Chondrou
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus.
| | - Malamati Kourti
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus.
| | - Ilias Georgakopoulos-Soares
- Institute for Personalized Medicine, Department of Biochemistry and Molecular Biology, The Pennsylvania State University College of Medicine, Hershey, PA, USA.
| | - Apostolos Zaravinos
- Department of Life Sciences, School of Sciences, European University Cyprus, Nicosia, Cyprus; Cancer Genetics, Genomics and Systems Biology Laboratory, Basic and Translational Cancer Research Center (BTCRC), Nicosia, Cyprus.
| |
Collapse
|
5
|
Autio KA, McHugh DJ, Rathkopf DE, Xiao H, Merugu S, Wong P, Jan M, Dorff TB, Heath EI, Scher HI. Olaparib and Durvalumab in Patients with DNA Damage Repair Alterations and Biochemically Recurrent Prostate Cancer. JOURNAL OF IMMUNOTHERAPY AND PRECISION ONCOLOGY 2025; 8:172-176. [PMID: 40270785 PMCID: PMC12010483 DOI: 10.36401/jipo-24-36] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/16/2024] [Revised: 01/20/2025] [Accepted: 01/28/2025] [Indexed: 04/25/2025]
Affiliation(s)
- Karen A. Autio
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Deaglan J. McHugh
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Dana E. Rathkopf
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Han Xiao
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
| | - Swathi Merugu
- Immune Monitoring Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Phillip Wong
- Immune Monitoring Facility, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mehrin Jan
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tanya B. Dorff
- Department of Medical Oncology & Experimental Therapeutics, City of Hope Comprehensive Cancer Center, Duarte, CA, USA
| | - Elisabeth I. Heath
- Karmanos Cancer Institute, Department of Oncology, Wayne State University School of Medicine, Detroit, MI, USA
| | - Howard I. Scher
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Weill Cornell Medical College, New York, NY, USA
- Biomarker Development Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| |
Collapse
|
6
|
Bossé Y, Boudreau DK, Saavedra Armero V, Li Z, Tremblay É, Gaudreault N, Gagné A, Desmeules P, Joubert P. Frequency of targetable genetic alterations in resectable lung adenocarcinoma: Results from the LORD project. Lung Cancer 2025; 203:108530. [PMID: 40209611 DOI: 10.1016/j.lungcan.2025.108530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2025] [Revised: 03/31/2025] [Accepted: 04/02/2025] [Indexed: 04/12/2025]
Abstract
There is still limited data on the prevalence of actionable molecular alterations in patients with early-stage resectable lung adenocarcinoma and prior studies reported important differences across geographic locations, demographic and pathologic characteristics. The tumors of 1,603 French Canadian patients with pathologically confirmed lung adenocarcinoma were interrogated using a 50-gene next-generation sequencing panel. The goal was to assess the prevalence of genetic alterations in eleven guideline-based oncogenic genes in resectable lung adenocarcinoma. Age, sex, pathological stage, smoking history and predominant histologic patterns were associated with molecular subtypes defined by oncogenic drivers. Age at surgery for the 1,603 patients was 65 ± 8 and includes 61 % of females, 6 % of patients without a smoking history and 70 % of stage I. The overall prevalence of targetable alterations for approved and investigational therapies was 65.9 % and 56.7 % of patients had tumors harboring at least one variant of strong clinical significance (tier I of the AMP/ASCO/CAP categorization). The most frequently mutated genes were KRAS (45.3 %), EGFR (11.5 %) and BRAF (3.9 %). MET exon 14 skipping alterations were identified in 47 patients (2.9 %) and oncogenic fusions in ALK, ROS1, RET and MET were found in 1.7 % of cases. As expected, EGFR activating mutations were associated with patients who never smoked, females, earlier disease stages, with more lepidic/acinar and less solid predominant patterns. Quasi similar but inverted relationships with clinico-pathological features were observed in one third of patients (n = 534) free of molecular alterations characterized by more males, patients who smoked, with later stage diagnosis and with more solid and less lepidic/acinar adenocarcinomas. This study highlights the epidemiology of guideline-based targetable alterations in French-Canadian patients with resectable lung adenocarcinoma. The large proportion of patients eligible for targeted therapies will have important impact on oncological practices in the current era of neoadjuvant and perioperative treatments.
Collapse
Affiliation(s)
- Yohan Bossé
- Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada; Department of Molecular Medicine, Université Laval, Quebec City, Canada.
| | - Dominique K Boudreau
- Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada
| | - Victoria Saavedra Armero
- Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada
| | - Zhonglin Li
- Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada
| | - Élody Tremblay
- Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada
| | - Nathalie Gaudreault
- Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada
| | - Andréanne Gagné
- Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada
| | - Patrice Desmeules
- Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada
| | - Philippe Joubert
- Institut universitaire de cardiologie et de pneumologie de Québec - Université Laval, Quebec City, Canada; Department of Molecular Biology, Pathology and Medical Biochemistry, Université Laval, Quebec City, Canada
| |
Collapse
|
7
|
Cho BC, Lu S, Lee MA, Song Z, Park JJ, Lim SM, Li Z, Zhao J, Richardson G, Zhang Y, Zhang J, Liu A, Loong HH, Chen C, Wang J, Shen Y, Fan Z, Chen Q, Wang H, Zhang J, Chen ZJ, Johnson ML, Mok T. D3S-001 in advanced solid tumors with KRAS G12C mutations: a phase 1 trial. Nat Med 2025:10.1038/s41591-025-03688-6. [PMID: 40301557 DOI: 10.1038/s41591-025-03688-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2025] [Accepted: 04/02/2025] [Indexed: 05/01/2025]
Abstract
D3S-001 is a next-generation KRAS-G12C inhibitor (G12Ci) designed to enhance target engagement efficiency and overcome growth factor-induced nucleotide exchange. D3S-001 was evaluated in a phase 1a dose-escalation study in patients with advanced solid tumors harboring KRASG12C mutation (N = 42) and a phase 1b expansion cohort of patients with non-small-cell lung cancer (NSCLC) whose disease progressed after prior G12Ci therapy (N = 20). The primary endpoints were safety and determination of the maximum tolerated dose. Secondary endpoints included pharmacokinetics, confirmed objective response rate (ORR) and disease control rate. D3S-001 demonstrated dose-dependent pharmacokinetics and no dose-limiting toxicities, and the maximum tolerated dose was not reached. Grade 3 treatment-related adverse events were reported in seven patients (16.7%) in the G12Ci-naive dose-escalation cohort and two patients (10.0%) in the G12Ci-pretreated NSCLC expansion cohort. There were no grade 4 or 5 treatment-related adverse events. D3S-001 600 mg was selected as the dose for further investigation based on pharmacokinetics. Confirmed ORR in the G12Ci-naive population was 73.5% overall (25 of 34), and 66.7% (14 of 21), 88.9% (8 of 9) and 75.0% (3 of 4) in patients with NSCLC, colorectal cancer and pancreatic ductal adenocarcinoma, respectively. Among patients with G12Ci-pretreated NSCLC, ORR was 30.0% (6 of 20) and disease control rate was 80.0% (16 of 20). This study demonstrates the safety and tolerability of D3S-001 monotherapy with promising antitumor activity. The phase 1b expansion phase is ongoing. ClinicalTrials.gov identifier: NCT05410145 .
Collapse
Affiliation(s)
- Byoung Chul Cho
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea.
| | - Shun Lu
- Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Myung Ah Lee
- Division of Medical Oncology, Cancer Research Institute, Seoul St. Mary's Hospital, The Catholic University of Korea, Seoul, South Korea
| | - Zhengbo Song
- Department of Chemotherapy, Zhejiang Cancer Hospital, Hangzhou, China
| | - John J Park
- Macquarie Medical School, Macquarie University, Sydney, New South Wales, Australia
| | - Sun Min Lim
- Division of Medical Oncology, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, South Korea
| | - Ziming Li
- Department of Medical Oncology, Shanghai Chest Hospital, Shanghai Jiao Tong University, School of Medicine, Shanghai, China
| | - Jun Zhao
- Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Thoracic Oncology, Peking University Cancer Hospital and Institute, Beijing, China
| | | | - Yanqiao Zhang
- Cancer Hospital Affiliated to Harbin Medical University, Harbin, China
| | - Jun Zhang
- Ruijin Hospital Affiliated to The Shanghai Jiao Tong University Medical School, Shanghai, China
| | - Anwen Liu
- 2nd Affiliated Hospital of Nanchang University, Nanchang, China
| | - Herbert H Loong
- The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Hong Kong, China
| | | | | | | | | | | | | | | | | | | | - Tony Mok
- The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Hong Kong, China
| |
Collapse
|
8
|
Slotkin EK, Mauguen A, Dela Cruz FS, Ortiz MV, Avutu V, Meyers PA, Wexler LH, O'Donohue TJ, Kinnaman MD, Kelly CM, D'Angelo SP, Keohan ML, Gounder MM, Thornton K, Nacev BA, Chi P, Rosenbaum E, Dickson M, Pachhal S, Somwar R, Ladanyi M, Robb C, Pandit-Taskar N, Hwang S, Price A, Behr G, Reed DR, Kentsis A, Kung AL, Bender JG, Tap WD. ACR-368, a CHK1/2 Kinase Inhibitor, in Patients With Relapsed or Refractory Desmoplastic Small Round Cell Tumor: Phase I/II Trial Results. JCO ONCOLOGY ADVANCES 2025; 2:e2400095. [PMID: 40330140 PMCID: PMC12052087 DOI: 10.1200/oa-24-00095] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Revised: 12/04/2024] [Accepted: 03/13/2025] [Indexed: 05/08/2025]
Abstract
PURPOSE We hypothesized that ACR-368 (prexasertib) would be active in desmoplastic small round cell tumor (DSRCT) because of favorable responses in preclinical models. METHODS Preclinical work identified ACR-368 activity in DSRCT, and a phase I/II trial of ACR-368 and irinotecan in patients 12 months and older with relapsed/refractory DSRCT was conducted. The primary objectives were determination of recommended phase II dose (RP2D) and best overall response rate (ORR) at the RP2D in DSRCT, with ≥3 of 16 responses considered promising. RESULTS Preclinical data confirmed ACR-368 as potentially therapeutic in DSRCT, and 19 patients were enrolled in a subsequent clinical trial. Treatment was well tolerated, and cytopenias were managed using growth factors. Fifteen of 19 patients, including five of six achieving PR, had previously received irinotecan. The estimated ORR at the RP2D was 23% (lower boundary one-sided 90% CI, 9%), exceeding the unpromising rate of 5%. In addition, three patients with DSRCT had a PR at doses other than the RP2D, bringing the ORR for all doses (n = 19) to 32% (90% CI, 15% to 53%). The median overall survival was 19 months (95% CI, 13 to 36). CONCLUSION The RP2D of ACR-368 with irinotecan by age group is ACR-368 105 or 150 mg/m2 once on day 1 (>21 years or ≤21 years, respectively) and irinotecan 15 mg/m2 once daily for 5 days in 21-day cycles for both groups. The study met its primary objective to consider ACR-368 and irinotecan promising in DSRCT and, to our knowledge, is the first incorporating a targeted therapy to achieve this magnitude of response.
Collapse
Affiliation(s)
- Emily K. Slotkin
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Audrey Mauguen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY
| | | | - Michael V. Ortiz
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Viswatej Avutu
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Paul A. Meyers
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Leonard H. Wexler
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Tara J. O'Donohue
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Michael D. Kinnaman
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ciara M. Kelly
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sandra P. D'Angelo
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mary Lou Keohan
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mrinal M. Gounder
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Katherine Thornton
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Benjamin A. Nacev
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ping Chi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Evan Rosenbaum
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Mark Dickson
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sagarika Pachhal
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Romel Somwar
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Marc Ladanyi
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Caroline Robb
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Neeta Pandit-Taskar
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Sinchun Hwang
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anita Price
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Gerald Behr
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Damon R. Reed
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Alex Kentsis
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Andrew L. Kung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Julia Glade Bender
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY
| | - William D. Tap
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| |
Collapse
|
9
|
Hui W, Lei KM, Liu Y, Huang X, Zhong Y, Chen X, Wei M, Yan J, Shen R, Mak PI, Martins RP, Yi S, Wang P, Jia Y. Identification and Drug Screening of Single Cells from Human Tumors on Semiconductor Chip for Cancer Precision Medicine. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025:e2503131. [PMID: 40271835 DOI: 10.1002/advs.202503131] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Revised: 04/02/2025] [Indexed: 04/25/2025]
Abstract
Drug screening of primary tumor cells directly assesses the drug efficacy on specific tumors, promoting personalized cancer treatment. The application of a microfluidic platform has realized drug screening using a limited amount of biopsy samples for cancer precision medicine. However, all the techniques face an inevitable issue of not all the primary tumor cells being cancer cells. Here, a system is introduced that integrates single-cell identification and drug screening on one semiconductor chip so that both drug efficacy on cancer cells and drug toxicity on noncancerous cells can be obtained simultaneously. An integrated circuit is built on the semiconductor chip for single-cell electric impedance sensing (IC-ECIS) of ultra-weak signals for distinguishing cancer cells from noncancerous cells without affecting cell vitality. Single-cell identification is validated using breast, lung, and liver cell lines as well as liver cancer specimens from clinical patients. The accuracy on commercial cell lines is ≈80%, and the diagnostic results of tumor tissues are consistent with clinical pathology results. Drug screening is run on the same chip after single cell identification for dual evaluation of drug efficacy and toxicity in both breast cancer models and clinical liver cancer patients. The on-chip drug screening is confirmed with off-chip counterpart experiments in breast cell lines. The effectiveness or ineffectiveness of a drug screened on the IC-ECIS chip demonstrated consistency in the presence or absence of specific mutations in the drug-related genes determined via exome sequencing of individual liver tumors, validating the method for precision medicine.
Collapse
Affiliation(s)
- Wenhao Hui
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Ka-Meng Lei
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Yingying Liu
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Xinru Huang
- Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510000, China
| | - Yunlong Zhong
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, China
| | - Xiaojun Chen
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Lingnan Normal University, Zhanjiang, 524000, China
| | - Mingji Wei
- Electrical and Information Engineering, Jiangsu University, Zhenjiang, 212000, China
| | - Jie Yan
- Department of Physics, National University of Singapore, Singapore, 546080, Singapore
- Mechanobiology Institute, National University of Singapore, Singapore, 546080, Singapore
| | - Ren Shen
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Pui-In Mak
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
| | - Rui P Martins
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
- On leave from Instituto Superior Tecnico, Universidade de Lisboa, Lisboa, 1649-004, Portugal
| | - Shuhong Yi
- Liver Transplantation Center, The Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou, 510000, China
| | - Ping Wang
- Department of Hepatobiliary Surgery, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510000, China
| | - Yanwei Jia
- State Key Laboratory of Analog and Mixed-Signal VLSI, Institute of Microelectronics, University of Macau, Taipa, 999078, Macau
- Faculty of Science and Technology, University of Macau, Taipa, 999078, Macau
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Taipa, 999078, Macau
| |
Collapse
|
10
|
Pich O, Bernard E, Zagorulya M, Rowan A, Pospori C, Slama R, Encabo HH, O’Sullivan J, Papazoglou D, Anastasiou P, Iliakis CS, Clark SA, Dijkstra KK, Barbè V, Bailey C, Stonestrom AJ, Enfield KS, Green M, Brierley CK, Magness A, Pearce DR, Hynds RE, Zaidi R, Rane JK, Álvarez-Prado ÁF, Thol K, Scott R, Bola SK, Hoxha E, Harris SK, Peggs KS, Quezada SA, Hackshaw A, Zaccaria S, Joyce JA, Malanchi I, Berger MF, Jamal-Hanjani M, Wack A, Downward J, Grey W, Lo Celso C, Gronroos E, Rudin CM, Mead AJ, Bonnet D, Papaemmanuil E, Swanton C. Tumor-Infiltrating Clonal Hematopoiesis. N Engl J Med 2025; 392:1594-1608. [PMID: 40267425 PMCID: PMC12021423 DOI: 10.1056/nejmoa2413361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 04/25/2025]
Abstract
BACKGROUND Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear. METHODS We characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors. RESULTS Among patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth. CONCLUSIONS TI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).
Collapse
Affiliation(s)
- Oriol Pich
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Elsa Bernard
- Computational Clinical Oncology Laboratory, UMR 981, Gustave Roussy, Villejuif, France
| | - Maria Zagorulya
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Andrew Rowan
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Constandina Pospori
- Bone Marrow Dynamics, The Francis Crick Institute, London, UK
- Imperial College London, London, UK
| | - Ramy Slama
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford
| | | | - Jennifer O’Sullivan
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford
| | - Despoina Papazoglou
- Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, UK
| | | | | | - Sally-Ann Clark
- Flow Cytometry Facility, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford
| | - Krijn K. Dijkstra
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- Department of Molecular Oncology and Immunology, the Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands
- Oncode Institute, Utrecht, the Netherlands
| | - Vittorio Barbè
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Chris Bailey
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Aaron J. Stonestrom
- Greenebaum Comprehensive Cancer Center, University of Maryland School of Medicine, Baltimore, USA
| | - Katey S.S. Enfield
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Mary Green
- Experimental Histopathology, The Francis Crick Institute, London, UK
| | - Charlotte K. Brierley
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford
- Oxford University Hospitals NHS Foundation Trust, Oxford, UK
| | - Alastair Magness
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - David R. Pearce
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- University College London Cancer Institute, London, UK
| | - Robert E. Hynds
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- University College London Cancer Institute, London, UK
| | - Rija Zaidi
- Computational Cancer Genomics Research Group, University College London Cancer Institute, London, UK
| | - Jayant K. Rane
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- University College London Cancer Institute, London, UK
| | - Ángel F. Álvarez-Prado
- Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne 1011, Lausanne, Switzerland
- Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland
- L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland
| | - Kerstin Thol
- Cancer Genome Evolution Research Group, Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
| | - Rachel Scott
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK
| | - Supreet Kaur. Bola
- Cancer Immunology Unit, Immune Regulation and Tumour Immunotherapy Group, Research Department of Haematology, University College London Cancer Institute, London, UK
| | - Elena Hoxha
- Cancer Immunology Unit, Immune Regulation and Tumour Immunotherapy Group, Research Department of Haematology, University College London Cancer Institute, London, UK
| | - Steve K. Harris
- University College London Hospitals Biomedical Research Centre, London, UK
- Institute of Health Informatics, University College London, London, UK
| | - Karl S. Peggs
- University College London Hospitals NHS Foundation Trust, London, UK
| | - Sergio A. Quezada
- Cancer Immunology Unit, Immune Regulation and Tumour Immunotherapy Group, Research Department of Haematology, University College London Cancer Institute, London, UK
| | - Allan Hackshaw
- Cancer Research UK & UCL Cancer Trials Centre, London, UK
| | - Simone Zaccaria
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Computational Cancer Genomics Research Group, University College London Cancer Institute, London, UK
| | - Johanna A. Joyce
- Department of Oncology, University of Lausanne, Lausanne 1011, Switzerland
- Ludwig Institute for Cancer Research, University of Lausanne 1011, Lausanne, Switzerland
- Agora Cancer Research Centre Lausanne, Lausanne 1011, Switzerland
- L. Lundin and Family Brain Tumor Research Center, Departments of Oncology and Clinical Neurosciences, Centre Hospitalier Universitaire Vaudois, Lausanne 1011, Switzerland
| | - Ilaria Malanchi
- Tumour-Host Interaction Laboratory, The Francis Crick Institute, London, UK
| | - Michael F. Berger
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Mariam Jamal-Hanjani
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK
- Department of Medical Oncology, University College London Hospitals, London, UK
| | - Andreas Wack
- Immunoregulation Laboratory, The Francis Crick Institute, London, UK
| | - Julian Downward
- Oncogene Biology Laboratory, The Francis Crick Institute, London UK
| | - William Grey
- Proteostem laboratory, Centre for Blood Research, York Biomedical Research Institute, Department of Biology, University of York, UK
| | - Cristina Lo Celso
- Bone Marrow Dynamics, The Francis Crick Institute, London, UK
- Imperial College London, London, UK
| | - Eva Gronroos
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
| | - Charles M. Rudin
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Adam J. Mead
- Haematopoietic Stem Cell Biology Laboratory, Medical Research Council Weatherall Institute of Molecular Medicine, University of Oxford, Oxford
| | - Dominique Bonnet
- Haematopoietic Stem Cell Laboratory, The Francis Crick Institute, London, UK
| | - Elli Papaemmanuil
- Computational Oncology Service, Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Charles Swanton
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK
- Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, London, UK
- Department of Medical Oncology, University College London Hospitals, London, UK
| |
Collapse
|
11
|
Ghoreyshi N, Heidari R, Farhadi A, Chamanara M, Farahani N, Vahidi M, Behroozi J. Next-generation sequencing in cancer diagnosis and treatment: clinical applications and future directions. Discov Oncol 2025; 16:578. [PMID: 40253661 PMCID: PMC12009796 DOI: 10.1007/s12672-025-01816-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2024] [Accepted: 01/15/2025] [Indexed: 04/22/2025] Open
Abstract
Next-generation sequencing (NGS) has emerged as a pivotal technology in the field of oncology, transforming the approach to cancer diagnosis and treatment. This paper provides a comprehensive overview of the integration of NGS into clinical settings, emphasizing its significant contributions to precision medicine. NGS enables detailed genomic profiling of tumors, identifying genetic alterations that drive cancer progression and facilitating personalized treatment plans targeting specific mutations, thereby improving patient outcomes. This capability facilitates the development of personalized treatment plans targeting specific mutations, leading to improved patient outcomes and the potential for better prognosis. The application of NGS extends beyond identifying actionable mutations; it is instrumental in detecting hereditary cancer syndromes, thus aiding in early diagnosis and preventive strategies. Furthermore, NGS plays a crucial role in monitoring minimal residual disease, offering a sensitive method to detect cancer recurrence at an early stage. Its use in guiding immunotherapy by identifying biomarkers that predict response to treatment is also highlighted. Ethical issues related to genetic testing, such as concerns around patient consent and data privacy, are also important considerations that need to be addressed for the broader implementation of NGS. These include the complexities of data interpretation, the need for robust bioinformatics support, cost considerations, and ethical issues related to genetic testing. Addressing these challenges is essential for the widespread adoption of NGS. Looking forward, advancements such as single-cell sequencing and liquid biopsies promise to further enhance the precision of cancer diagnostics and treatment. This review emphasizes the transformative impact of NGS in oncology and advocates for its incorporation into routine clinical practice to promote molecularly driven cancer care.
Collapse
Affiliation(s)
- Nima Ghoreyshi
- Cancer Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Reza Heidari
- Cancer Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Arezoo Farhadi
- Department of Genetics and Molecular Medicine, School of Medicine, Zanjan University of Medical Sciences, Zanjan, Iran
| | - Mohsen Chamanara
- Department of Clinical Pharmacy, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran
- Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran
| | - Nastaran Farahani
- Department of Genetics and Biotechnology, Faculty of Life Science, Varamin-Pishva Branch, Islamic Azad University, Varamin, Iran
| | - Mahmood Vahidi
- Cancer Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran.
- Department of Medical Laboratory Sciences, School of Allied Health Medicine, AJA University of Medical Sciences, Tehran, Iran.
| | - Javad Behroozi
- Cancer Epidemiology Research Center, AJA University of Medical Sciences, Tehran, Iran.
- Department of Medical Genetics, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.
| |
Collapse
|
12
|
Campanella G, Chen S, Singh M, Verma R, Muehlstedt S, Zeng J, Stock A, Croken M, Veremis B, Elmas A, Shujski I, Neittaanmäki N, Huang KL, Kwan R, Houldsworth J, Schoenfeld AJ, Vanderbilt C. A clinical benchmark of public self-supervised pathology foundation models. Nat Commun 2025; 16:3640. [PMID: 40240324 PMCID: PMC12003829 DOI: 10.1038/s41467-025-58796-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 04/02/2025] [Indexed: 04/18/2025] Open
Abstract
The use of self-supervised learning to train pathology foundation models has increased substantially in the past few years. Notably, several models trained on large quantities of clinical data have been made publicly available in recent months. This will significantly enhance scientific research in computational pathology and help bridge the gap between research and clinical deployment. With the increase in availability of public foundation models of different sizes, trained using different algorithms on different datasets, it becomes important to establish a benchmark to compare the performance of such models on a variety of clinically relevant tasks spanning multiple organs and diseases. In this work, we present a collection of pathology datasets comprising clinical slides associated with clinically relevant endpoints including cancer diagnoses and a variety of biomarkers generated during standard hospital operation from three medical centers. We leverage these datasets to systematically assess the performance of public pathology foundation models and provide insights into best practices for training foundation models and selecting appropriate pretrained models. To enable the community to evaluate their models on our clinical datasets, we make available an automated benchmarking pipeline for external use.
Collapse
Affiliation(s)
- Gabriele Campanella
- Windreich Department of AI and Human Health, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
- Hasso Plattner Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA.
| | - Shengjia Chen
- Windreich Department of AI and Human Health, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
- Hasso Plattner Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Manbir Singh
- Windreich Department of AI and Human Health, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
- Hasso Plattner Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Ruchika Verma
- Windreich Department of AI and Human Health, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
- Hasso Plattner Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Silke Muehlstedt
- Windreich Department of AI and Human Health, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
- Hasso Plattner Institute at Mount Sinai, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Jennifer Zeng
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Aryeh Stock
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Matt Croken
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Brandon Veremis
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Abdulkadir Elmas
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Ivan Shujski
- Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Laboratory Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Noora Neittaanmäki
- Department of Clinical Pathology, Sahlgrenska University Hospital, Gothenburg, Sweden
- Department of Laboratory Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Kuan-Lin Huang
- Department of Genetics and Genomics, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Ricky Kwan
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Jane Houldsworth
- Department of Pathology, Icahn School of Medicine at Mount Sinai, New York, 10029, NY, USA
| | - Adam J Schoenfeld
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA
| | - Chad Vanderbilt
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, 10065, NY, USA.
| |
Collapse
|
13
|
Wang JJ, Huang RR, Cone BD, Kang SHL, Setoodeh R, Sisk AE, Sajed DP, Shuch BM, Sowalsky AG, Ye H. ELOC-Mutated Renal Cell Carcinoma is a Rare Indolent Tumor With Distinctive Genomic Characteristics. Mod Pathol 2025; 38:100777. [PMID: 40246078 DOI: 10.1016/j.modpat.2025.100777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2024] [Revised: 03/19/2025] [Accepted: 03/19/2025] [Indexed: 04/19/2025]
Abstract
ELOC-mutated renal cell carcinoma (ELOC-RCC) is a subtype of RCC first recognized by the World Health Organization in 2022, molecularly defined by the presence of ELOC mutations and the lack of VHL mutations. Here, we present an institutional series of ELOC-RCC and provide an in-depth genetic comparison to VHL-null clear cell RCC (VHL-ccRCCs). Among 1209 RCCs in our institutional cytogenetics database, we identified 16 candidate cases that were originally classified as ccRCC and exhibited monosomy 8 and intact chromosome 3p. Seven of these 16 candidate cases were diagnosed as ELOC-RCCs based on histomorphology, immunohistochemistry, and whole-exome sequencing results. By contrast, ELOC-RCCs had a simpler karyotype of monosomy 8 with few other alterations. Adding 6 additional ELOC-RCC cases identified from The Cancer Genome Atlas cohort, all 13 ELOC-RCCs exhibited biallelic ELOC inactivation without VHL mutations. These ELOC mutations (Y79C/L/S/N, E92K, A106D, and C112Vfs∗3) were all located within or close to the VHL-binding domains in ELOC protein; 69% of the ELOC-RCC cases exhibited its characteristic histomorphology. Compared with stage- and grade-matched VHL-ccRCCs, patients with ELOC-RCCs had superior overall survival (hazard ratio, 0.32; 95% confidence intervals, 0.16-0.61; P = .02) and progression-free survival (hazard ratio, 0.16; 95% confidence intervals, 0.06-0.42; P = 0.04). ELOC-RCCs had significantly fewer somatic copy number alterations and a greater abundance of the mutational signature SBS1 than VHL-ccRCCs. ELOC-RCCs lacked common chromosomal alterations or gene mutations seen in ccRCC, including PBRM1, SETD2, BAP1, TSC1, TSC2, or mTOR. Most ELOC-RCCs had linear phylogenetic trees with clonal and truncal ELOC mutations, whereas additional alterations to ELOC or 8q losses occurred as a subclonal event. Although 11 of 13 ELOC-RCCs were confined to the kidney, 2 ELOC-RCCs were high-stage and exhibited a large solid alveolar pattern, tumor necrosis, more somatic copy number alterations, and an additional monoallelic VHL copy loss. Taken together, ELOC-RCCs exhibit distinctive genomic features and indolent behavior in general, supporting it as an independent diagnostic entity.
Collapse
Affiliation(s)
- Jasmine J Wang
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Rong Rong Huang
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California
| | - Brian D Cone
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California
| | - Sung-Hae L Kang
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California
| | - Reza Setoodeh
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California
| | - Anthony E Sisk
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California
| | - Dipti P Sajed
- Department of Pathology and Laboratory Medicine, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California
| | - Brian M Shuch
- Department of Urology, University of California Los Angeles, David Geffen School of Medicine, Los Angeles, California.
| | - Adam G Sowalsky
- Genitourinary Malignancies Branch, National Cancer Institute, Bethesda, Maryland.
| | - Huihui Ye
- Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, California.
| |
Collapse
|
14
|
Liu J, Wang Z. The landscape of FGFR-TACC fusion in adult glioblastoma: From bench to bedside. MUTATION RESEARCH. REVIEWS IN MUTATION RESEARCH 2025; 795:108536. [PMID: 40246063 DOI: 10.1016/j.mrrev.2025.108536] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 04/14/2025] [Accepted: 04/14/2025] [Indexed: 04/19/2025]
Abstract
Glioblastoma (GBM) is a lethal central nervous system tumor, characterized by extensive genomic alterations and high intra-tumoral heterogeneity. Gene fusions, derived from chromosomal translocations, deletions, and inversions, were increasingly recognized as key carcinogenic events, with the highest frequency of FGFR-TACC fusion in glioblastoma. As reported, FGFR3-TACC3 fusion mostly coexists with wild-type IDH status, and associates with better prognosis. Mechanistically, FGFR3-TACC3 fusions can constitutively activate non-canonical FGFR downstream pathways, induce aneuploidy, and participate in mitochondrial metabolism, thereby promoting cell proliferation and tumorigenesis. These functions, whether based on FGFR3 phosphorylation or not, are predominantly attributed to the specific domain of TACC3 that involved in regulating the localization and activation of fusion products. Several preclinical studies and clinical trials are being performed to evaluate the efficacy and safety of the FGFR-TACC fusion as a personalised therapeutic target, including the treatments with tyrosine kinase inhibitors, metabolic inhibitors, HSP90 inhibitors, coiled-coil peptide-mimetics, and targeted protein degraders. A subset of populations with FGFR-TACC-positive glioblastoma, after refined molecular screening strategies, may benefit from targeted therapies. Despite major progress in biotechnology, our understanding on the role of fusion events in glioblastoma represented by the FGFR-TACC is still in its infancy. Here, we highlight recent progress on FGFR-TACC fusion in human glioblastoma, emphasizing their molecular mechanisms and potential clinical value.
Collapse
Affiliation(s)
- Jing Liu
- Department of Radiotherapy, Tianjin First Central Hospital, Nankai University, Tianjin 300384, China
| | - Zheng Wang
- Department of Radiotherapy, Tianjin First Central Hospital, Nankai University, Tianjin 300384, China.
| |
Collapse
|
15
|
Liu SV, Nagasaka M, Atz J, Solca F, Müllauer L. Oncogenic gene fusions in cancer: from biology to therapy. Signal Transduct Target Ther 2025; 10:111. [PMID: 40223139 PMCID: PMC11994825 DOI: 10.1038/s41392-025-02161-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2024] [Revised: 12/06/2024] [Accepted: 01/16/2025] [Indexed: 04/15/2025] Open
Abstract
Oncogenic gene fusions occur across a broad range of cancers and are a defining feature of some cancer types. Cancers driven by gene fusion products tend to respond well to targeted therapies, where available; thus, detection of potentially targetable oncogenic fusions is necessary to select optimal treatment. Detection methods include non-sequencing methods, such as fluorescence in situ hybridization and immunohistochemistry, and sequencing methods, such as DNA- and RNA-based next-generation sequencing (NGS). While NGS is an efficient way to analyze multiple genes of interest at once, economic and technical factors may preclude its use in routine care globally, despite several guideline recommendations. The aim of this review is to present a summary of oncogenic gene fusions, with a focus on fusions that affect tyrosine kinase signaling, and to highlight the importance of testing for oncogenic fusions. We present an overview of the identification of oncogenic gene fusions and therapies approved for the treatment of cancers harboring gene fusions, and summarize data regarding treating fusion-positive cancers with no current targeted therapies and clinical studies of fusion-positive cancers. Although treatment options may be limited for patients with rare alterations, healthcare professionals should identify patients most likely to benefit from oncogenic gene fusion testing and initiate the appropriate targeted therapy to achieve optimal treatment outcomes.
Collapse
Affiliation(s)
- Stephen V Liu
- Division of Hematology and Oncology, Georgetown University, Washington, DC, USA.
| | - Misako Nagasaka
- Division of Hematology Oncology, Department of Medicine, University of California Irvine School of Medicine, Irvine, CA, USA
- Chao Family Comprehensive Cancer Center, Orange, CA, USA
| | - Judith Atz
- Boehringer Ingelheim International GmbH, Ingelheim am Rhein, Germany
| | - Flavio Solca
- Boehringer Ingelheim RCV GmbH & Co.KG, Vienna, Austria
| | - Leonhard Müllauer
- Department of Pathology, Medical University of Vienna, 1090, Vienna, Austria
| |
Collapse
|
16
|
Nørgaard M, Rusan M, Kondrup K, Sørensen EMG, Weiss S, Bjerre MT, Fredsøe J, Vang S, Jensen JB, De Laere B, Grönberg H, Borre M, Lindberg J, Sørensen KD. Deep targeted sequencing of circulating tumor DNA to inform treatment in patients with metastatic castration-resistant prostate cancer. J Exp Clin Cancer Res 2025; 44:120. [PMID: 40229848 PMCID: PMC11998381 DOI: 10.1186/s13046-025-03356-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 03/04/2025] [Indexed: 04/16/2025] Open
Abstract
BACKGROUND Intrinsic and acquired resistance to second-generation anti-androgens pose a significant clinical challenge in the treatment of metastatic castration-resistant prostate cancer (mCRPC). Novel biomarkers to predict treatment response and inform alternative treatment options are urgently needed. METHODS Deep targeted sequencing, with a prostate cancer-specific gene panel, was performed on circulating tumor DNA (ctDNA) and germline DNA from blood of mCRPC patients recruited in Denmark (n = 53), prior to starting first-line treatment with enzalutamide or abiraterone acetate, and for a subset of patients also at progression (n = 18). Likely clonal hematopoietic variants were filtered out. Genomic findings were correlated to clinical outcomes (PSA progression-free survival (PFS), overall survival (OS)). Intrinsic resistance candidate biomarkers were considered by enrichment analysis of nonresponders vs. responders. Genomic alterations at progression were considered as possible drivers of acquired resistance. Clinical actionability was assessed based on OncoKB and ESCAT. RESULTS Somatic alterations in PTEN, cell cycle regulators (CCND1, CDKN1B, CDKN2A, and RB1) and chromatin modulators (CHD1, ARID1A) were associated with significantly shorter PFS and OS, also after adjusting for ctDNA% in multivariate Cox regression analysis. The associations with poorer outcomes for alterations in PTEN and chromatin modulators were validated in an external dataset. Patients with primary resistance to enzalutamide/abiraterone had enrichment for BRAF amplification and CHD1 loss, while responders had enrichment for TMPRSS2 fusions. AR resistance mutations emerged in 22% of patients at progression. These were mutually exclusive with other alterations that may confer resistance (i.e., activating CTNNB1 mutations, combined TP53/RB1 loss). Clinically actionable alterations, primarily in homologous recombination repair genes, were found in 54.7% and 49.0% of patients (OncoKB and ESCAT, respectively), with few additional alterations detected at progression. Level I alterations were identified in 41.5% of patients employing OncoKB, however only in 13.2% based on ESCAT. CONCLUSIONS Our study identifies known and novel prognostic and predictive biomarker candidates in patients with mCRPC undergoing first-line treatment with enzalutamide or abiraterone acetate. It further provides real-world evidence of the significant potential of genomic profiling of ctDNA to inform treatment in this setting. Clinical trials are warranted to advance the implementation of ctDNA-based biomarkers into clinical practice.
Collapse
Affiliation(s)
- Maibritt Nørgaard
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Maria Rusan
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Clinical Pharmacology, Aarhus University Hospital, Aarhus, Denmark
| | - Karoline Kondrup
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Ea Marie Givskov Sørensen
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Simone Weiss
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Marianne Trier Bjerre
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Urology, Aarhus University Hospital, Aarhus, Denmark
- Department of Urology, Gødstrup Hospital, Gødstrup, Denmark
| | - Jacob Fredsøe
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Søren Vang
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
| | - Jørgen Bjerggaard Jensen
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Urology, Gødstrup Hospital, Gødstrup, Denmark
| | - Bram De Laere
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium
- Cancer Research Institute Gent (CRIG), Ghent University, Ghent, Belgium
| | - Henrik Grönberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Michael Borre
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark
- Department of Urology, Aarhus University Hospital, Aarhus, Denmark
| | - Johan Lindberg
- Department of Medical Epidemiology and Biostatistics, Karolinska Institutet, Stockholm, Sweden
| | - Karina Dalsgaard Sørensen
- Department of Molecular Medicine, Aarhus University Hospital, Palle Juul-Jensens Boulevard 99, Aarhus, 8200, Denmark.
- Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
| |
Collapse
|
17
|
Kato M, Nishino J, Nagai M, Rokutan H, Narushima D, Ono H, Hasegawa T, Imoto S, Matsui S, Tsunoda T, Shibata T. Comprehensive analysis of prognosis markers with molecular features derived from pan-cancer whole-genome sequences. Hum Genomics 2025; 19:39. [PMID: 40221813 PMCID: PMC11993945 DOI: 10.1186/s40246-025-00744-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2024] [Accepted: 03/19/2025] [Indexed: 04/14/2025] Open
Abstract
Cancer prognosis markers are useful for treatment decisions; however, the omics-level landscape is not well understood across multiple cancer types. Pan-Cancer Analysis of Whole Genomes (PCAWG) provides unprecedented access to various types of molecular data, ranging from typical DNA mutations and RNA expressions to more deeply analyzed or whole-genomic features, such as HLA haplotypes and structural variations. We analyzed the PCAWG data of 13 cancer types from 1,514 patients to identify prognosis markers belonging to 17 molecular features in the survival analysis based on the Cox and Lasso regression methods. We found that germline features including HLA haplotypes, neoantigens, and the number of structural variations were associated with overall survival; however, mutational signatures were not. Measuring a few markers provided a sufficient prognostic performance evaluated by c-index for each cancer type. DNA markers demonstrated better or comparable prognostic performance compared to RNA markers in some cancer types. "Universal" markers strongly associated with overall survival across cancer types were not identified. These findings will give insights into the clinical implementation of prognosis markers.
Collapse
Affiliation(s)
- Mamoru Kato
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan.
- CREST, JST, Tokyo, Japan.
| | - Jo Nishino
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan
- CREST, JST, Tokyo, Japan
| | - Momoko Nagai
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan
- CREST, JST, Tokyo, Japan
| | - Hirofumi Rokutan
- Division of Cancer Genomics, Research Institute, National Cancer Center Japan, Tokyo, Japan
| | - Daichi Narushima
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan
| | - Hanako Ono
- Division of Bioinformatics, Research Institute, National Cancer Center Japan, Tokyo, Japan
| | - Takanori Hasegawa
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Seiya Imoto
- Division of Health Medical Intelligence, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| | - Shigeyuki Matsui
- CREST, JST, Tokyo, Japan
- Department of Biostatistics, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tatsuhiko Tsunoda
- CREST, JST, Tokyo, Japan
- Laboratory for Medical Science Mathematics, Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo, Japan
- Laboratory for Medical Science Mathematics, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Tatsuhiro Shibata
- Division of Cancer Genomics, Research Institute, National Cancer Center Japan, Tokyo, Japan
- Laboratory of Molecular Medicine, Human Genome Center, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan
| |
Collapse
|
18
|
Rafiee A, Nasri P, Moradi A, Karimian P. Tumor budding as an indicator of prognosis in locally advanced rectal cancer after neoadjuvant chemoradiotherapy: a systematic review and meta-analysis. Front Oncol 2025; 15:1429319. [PMID: 40270611 PMCID: PMC12014445 DOI: 10.3389/fonc.2025.1429319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Accepted: 02/24/2025] [Indexed: 04/25/2025] Open
Abstract
Introduction Tumor budding (TB) is recognized as a complementary prognostic factor for colorectal cancer. However, data on its impact on the survival of patients undergoing neoadjuvant chemoradiotherapy (nCRT) remain limited. This study aims to investigate the role of TB in disease-free survival (DFS) and overall survival (OS) among patients with locally advanced rectal cancer receiving nCRT. Methods In this systematic review and meta-analysis, an exhaustive search of the PubMed, Scopus, Web of Science (WOS), Embase, and Cochrane databases was conducted, ultimately leading to the extraction of eight studies in the qualitative assessment and meta-analysis. Results All the included studies were of high quality. The total sample size comprised 1,941 individuals. Although eight studies were included, nine datasets were extracted, as some studies reported multiple outcome measurements. TB positivity was statistically associated with decreased overall survival of 3.24 (95% confidence interval [CI]: 1.71-6.16) and disease-free survival of 2.54 (95% CI: 1.56-4.15) in patients with locally advanced rectal cancer undergoing nCRT. Discussion Based on the findings of this study, TB negativity was statistically and directly associated with better OS and DFS in patients with locally advanced rectal cancer undergoing nCRT.
Collapse
Affiliation(s)
- Azita Rafiee
- Department of Pathology, Iranian Medical and Pathology Laboratory, Zahedan, Iran
| | - Parto Nasri
- Department of Pathology, Isfahan University of Medical Sciences, Isfahan, Iran
| | - Afshin Moradi
- Cancer Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Paridokht Karimian
- Department of Pathology, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
| |
Collapse
|
19
|
Trédan O, Pouessel D, Penel N, Chabaud S, Gomez-Roca C, Delord JP, Pannier D, Brahmi M, Fabbro M, Garcia ME, Larrieu-Ciron D, Ray-Coquard I, Viala M, Italiano A, Tosi D, Cassier P, Dufresne A, Attignon V, Boyault S, Treilleux I, Viari A, Pérol D, Blay JY. Broad versus limited gene panels to guide treatment in patients with advanced solid tumors: a randomized controlled trial. Nat Med 2025:10.1038/s41591-025-03613-x. [PMID: 40195451 DOI: 10.1038/s41591-025-03613-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Accepted: 02/26/2025] [Indexed: 04/09/2025]
Abstract
Large genomic programs have contributed to improving drug development in cancer. To assess the potential benefit of using larger gene panels to guide molecular-based treatments, we conducted a multicenter randomized trial in patients with advanced and/or metastatic solid cancer. Molecular alterations were determined using either a panel of 324 cancer-related genes (Foundation OneCDX (F1CDX)) or a limited panel of 87 single-nucleotide/indel genes and genome-wide copy number variations (CTL) and reviewed by a molecular tumor board to identify molecular-based recommended therapies (MBRTs). Using paired data from both panels for each patient, the primary endpoint was the proportion of patients with an MBRT identified. Main secondary endpoints included the number of patients with at least one actionable alteration leading to MBRT identification, the number of patients with and without MBRTs initiated, progression-free survival, best overall response, duration of response and safety. Among the 741 patients screened, 45.7% had quality-checked tumor samples. MBRTs were identified with F1CDX in 175 (51.6%) patients and with CTL in 125 (36.9%) patients, translating to a significant increase of 14.8 percentage points (P < 0.001) with the more comprehensive gene panel versus the more limited panel, meeting the primary endpoint. However, no differences in clinical outcomes were observed in these patients with advanced and/or metastatic cancer in need of treatment beyond standard genomic alterations. These findings illustrate the potential for larger gene panels to increase the number of molecularly matched therapies. Larger studies are needed to assess the clinical benefit of expanded MBRTs. ClinicalTrials.gov registration: NCT03163732 .
Collapse
Affiliation(s)
- Olivier Trédan
- Centre Léon Bérard, Lyon, France.
- Cancer Research Center of Lyon, Lyon, France.
| | | | - Nicolas Penel
- Centre Oscar Lambret, Lille and Université de Lille ULR 2694, Lille, France
| | | | | | | | - Diane Pannier
- Centre Oscar Lambret, Lille and Université de Lille ULR 2694, Lille, France
| | | | - Michel Fabbro
- Institut de Cancérologie de Montpellier, Montpellier, France
| | | | | | | | - Marie Viala
- Institut de Cancérologie de Montpellier, Montpellier, France
| | | | - Diego Tosi
- Institut de Cancérologie de Montpellier, Montpellier, France
| | | | | | | | - Sandrine Boyault
- Centre Léon Bérard, Lyon, France
- Cancer Research Center of Lyon, Lyon, France
| | | | - Alain Viari
- Centre Léon Bérard, Lyon, France
- INRIA, Grenoble, France
| | | | - Jean Yves Blay
- Centre Léon Bérard, Lyon, France
- Cancer Research Center of Lyon, Lyon, France
- Université Claude Bernard Lyon I, Lyon, France
| |
Collapse
|
20
|
Vicario R, Fragkogianni S, Pokrovskii M, Meyer C, Lopez-Rodrigo E, Hu Y, Ogishi M, Alberdi A, Baako A, Ay O, Plu I, Sazdovitch V, Heritier S, Cohen-Aubart F, Shor N, Miyara M, Nguyen-Khac F, Viale A, Idbaih A, Amoura Z, Rosenblum MK, Zhang H, Karnoub ER, Sashittal P, Jakatdar A, Iacobuzio-Donahue CA, Abdel-Wahab O, Tabar V, Socci ND, Elemento O, Diamond EL, Boisson B, Casanova JL, Seilhean D, Haroche J, Donadieu J, Geissmann F. Role of clonal inflammatory microglia in histiocytosis-associated neurodegeneration. Neuron 2025; 113:1065-1081.e13. [PMID: 40081365 DOI: 10.1016/j.neuron.2025.02.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2023] [Revised: 10/28/2024] [Accepted: 02/10/2025] [Indexed: 03/16/2025]
Abstract
Langerhans cell histiocytosis (LCH) and Erdheim-Chester disease (ECD) are clonal myeloid disorders associated with mitogen-activated protein (MAP)-kinase-activating mutations and an increased risk of neurodegeneration. We found microglial mutant clones in LCH and ECD patients, whether or not they presented with clinical symptoms of neurodegeneration, associated with microgliosis, astrocytosis, and neuronal loss, predominantly in the rhombencephalon gray nuclei. Neurological symptoms were associated with PU.1+ clone size (p = 0.0003) in patients with the longest evolution of the disease, indicating a phase of subclinical incipient neurodegeneration. Genetic barcoding analysis suggests that clones may originate from definitive or yolk sac hematopoiesis, depending on the patients. In a mouse model, disease topography was attributable to a local clonal proliferative advantage, and microglia depletion by a CSF1R-inhibitor limited neuronal loss and improved survival. These studies characterize a neurodegenerative disease associated with clonal proliferation of inflammatory microglia. The long preclinical stage represents a therapeutic window before irreversible neuronal depletion.
Collapse
Affiliation(s)
- Rocio Vicario
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Stamatina Fragkogianni
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Maria Pokrovskii
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Carina Meyer
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Estibaliz Lopez-Rodrigo
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Yang Hu
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell, New York, NY 10021, USA
| | - Masato Ogishi
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
| | - Araitz Alberdi
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Ann Baako
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Oyku Ay
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - Isabelle Plu
- Department of Neuropathology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Véronique Sazdovitch
- Department of Neuropathology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Sebastien Heritier
- French Langerhans cell histiocytosis registry, Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France
| | - Fleur Cohen-Aubart
- Department of Internal Medicine & Institut E3M, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Natalia Shor
- Department of Neuroradiology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Makoto Miyara
- Center for Immunology and Infectious Diseases (CIMI-PARIS), Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Florence Nguyen-Khac
- Department of Hematology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Agnes Viale
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, MSKCC, New York, NY 10065, USA
| | - Ahmed Idbaih
- Sorbonne Université, Inserm, CNRS, UMR S 1127, Institut du Cerveau et de la Moelle épinière, ICM, AP-HP, Hôpitaux Universitaires La Pitié-Salpêtrière - Charles Foix, Service de Neurologie 2-Mazarin, 75013 Paris, France
| | - Zahir Amoura
- Department of Neuroradiology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | | | - Haochen Zhang
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA
| | | | - Palash Sashittal
- Department of Computer Science, Princeton University, Princeton, NJ, USA
| | - Akhil Jakatdar
- Department of Computer Science, Princeton University, Princeton, NJ, USA
| | - Christine A Iacobuzio-Donahue
- Department of Pathology, MSKCC, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA
| | - Omar Abdel-Wahab
- Human Oncology and Pathogenesis Program, MSKCC, New York, NY, USA
| | - Viviane Tabar
- Department of Neurosurgery, and Center for Stem Cell Biology, MSKCC, New York, NY, USA; Department of Neurology, MSKCC, New York, NY 10065, USA
| | - Nicholas D Socci
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, MSKCC, New York, NY 10065, USA
| | - Olivier Elemento
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell, New York, NY 10021, USA
| | - Eli L Diamond
- Department of Neurosurgery, and Center for Stem Cell Biology, MSKCC, New York, NY, USA
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New York, NY 10065, USA
| | - Danielle Seilhean
- Department of Neuropathology, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France
| | - Julien Haroche
- Department of Internal Medicine & Institut E3M, Pitié-Salpêtrière Hospital, APHP-Sorbonne Université, Paris, France.
| | - Jean Donadieu
- French Langerhans cell histiocytosis registry, Department of Pediatric Hematology and Oncology, Trousseau Hospital, AP-HP, Paris, France
| | - Frederic Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
| |
Collapse
|
21
|
Soliman N, Maqsood A, Connor AA. Role of genomics in liver transplantation for cholangiocarcinoma. Curr Opin Organ Transplant 2025; 30:158-170. [PMID: 39917813 DOI: 10.1097/mot.0000000000001209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/06/2025]
Abstract
PURPOSE OF REVIEW The purpose of this review is to summarize the current knowledge of cholangiocarcinoma molecular biology and to suggest a framework for implementation of next-generation sequencing in all stages of liver transplantation. This is timely as recent guidelines recommend increased use of these technologies with promising results. RECENT FINDINGS The main themes covered here address germline and somatic genetic alterations recently discovered in cholangiocarcinoma, particularly those associated with prognosis and treatment responses, and nascent efforts to translate these into contemporary practice in the peri-liver transplantation period. SUMMARY Early efforts to translate molecular profiling to cholangiocarcinoma care demonstrate a growing number of potentially actionable alterations. Still lacking is a consensus on what biomarkers and technologies to adopt, at what scale and cost, and how to integrate them most effectively into care with the ambition of increasing the number of patients eligible for liver transplantation and improving their long-term outcomes.
Collapse
Affiliation(s)
- Nadine Soliman
- Department of Surgery
- J. C. Walter Jr. Transplant Center, Houston Methodist Hospital
- Houston Methodist Academic Institute
| | - Anaum Maqsood
- Department of Medicine
- Neill Cancer Center, Houston Methodist Hospital, Houston, Texas
| | - Ashton A Connor
- Department of Surgery
- J. C. Walter Jr. Transplant Center, Houston Methodist Hospital
- Houston Methodist Academic Institute
- Neill Cancer Center, Houston Methodist Hospital, Houston, Texas
- Department of Surgery, Weill Cornell Medicine, Cornell University, New York, New York, USA
| |
Collapse
|
22
|
Xiong Y, Li J, Jin W, Sheng X, Peng H, Wang Z, Jia C, Zhuo L, Zhang Y, Huang J, Zhai M, Lyu B, Sun J, Zhou M. PCMR: a comprehensive precancerous molecular resource. Sci Data 2025; 12:551. [PMID: 40169679 PMCID: PMC11961594 DOI: 10.1038/s41597-025-04899-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2024] [Accepted: 03/25/2025] [Indexed: 04/03/2025] Open
Abstract
Early detection and intervention of precancerous lesions are crucial in reducing cancer morbidity and mortality. Comprehensive analysis of genomic, transcriptomic, proteomic and epigenomic alterations can provide insights into the early stages of carcinogenesis. However, the lacke of an integrated, well-curated data resource of molecular signatures limits our understanding of precancerous processes. Here, we introduce a comprehensive PreCancerous Molecular Resource (PCMR), which compiles 25,828 molecular profiles of precancerous samples paired with normal or malignant counterparts. These profiles cover precancerous lesions of 35 cancer types across 20 organs and tissues, derived from tissue samples, liquid biopsies, cell lines and organoids, with data from transcriptomics, proteomics and epigenomics. PCMR includes 62,566 precancer-gene associations derived from differential analysis and text-mining using the ChatGPT large language model. We examined PCMR dataset reliability and significance by the authoritative precancerous molecular signature, along with its biological and clinical relevance. Overall, PCMR will serve as a valuable resource for advancing precancer research and ultimately improving patient outcomes.
Collapse
Affiliation(s)
- Yichun Xiong
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Jiaqi Li
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Wang Jin
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Xiaoran Sheng
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Hui Peng
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Zhiyi Wang
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Caifeng Jia
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Lili Zhuo
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Yibo Zhang
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Jingzhe Huang
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Modi Zhai
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Beibei Lyu
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China
| | - Jie Sun
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China.
| | - Meng Zhou
- School of Biomedical Engineering, Eye Hospital, Wenzhou Medical University, Wenzhou, 325027, P. R. China.
| |
Collapse
|
23
|
Pamuk E, Simon C. When neck lymph nodes metastases do not origin from a head and neck unknown primary. Curr Opin Otolaryngol Head Neck Surg 2025; 33:102-108. [PMID: 39838587 PMCID: PMC11888826 DOI: 10.1097/moo.0000000000001031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2025]
Abstract
PURPOSE OF REVIEW The evidence for a standardized approach to the management of cervical metastasis from a distant primary tumour is limited. The objective of this review is to provide an overview of the current status of research in this field and to present the latest diagnostic and therapeutic approaches. RECENT FINDINGS Although infraclavicular tumours are typically observed to metastasise to levels IV and V of the neck, all levels may potentially be affected. In conjunction with imaging and immunohistochemical analyses, next-generation sequencing and artificial intelligence-based tools are emerging as potential methods for identifying the primary tumour. Cervical metastasis can be classified as N3 or M1 in accordance with the histology and site of the primary tumour. A neck dissection + adjuvant chemoradiotherapy may prove beneficial in selected patients with breast, nonsmall cell lung, renal cell, oesophageal and testicular cancers, resulting in improved survival rates. SUMMARY The diagnosis and subsequent treatment of such cases requires the input of a multidisciplinary team, as the condition is often complex and requires a multifaceted approach. Isolated supraclavicular metastases should prompt the clinician to investigate a distant primary. In select patients with some types of primary tumours, surgical treatment of the neck may improve the prognosis. It is, therefore, essential to control the primary tumour in order to optimize the success of the overall treatment plan.
Collapse
Affiliation(s)
- Erim Pamuk
- Service d'Oto-rhino-laryngologie - Chirurgie cervico-faciale, Centre Hospitalier Universitaire Vaudois (CHUV), Université de Lausanne (UNIL), Lausanne, Switzerland
| | | |
Collapse
|
24
|
Fujisawa T, Nakamura Y, Bando H, Morizane C, Ikeda M, Nonomura N, Matsubara N, Iwata H, Naito Y, Okano S, Aoki D, Harano K, Yamazaki N, Namikawa K, Ueno M, Kadowaki S, Oki E, Kato K, Komatsu Y, Satoh T, Esaki T, Denda T, Hamaguchi T, Yamazaki K, Matsuhashi N, Yasui H, Satake H, Nishina T, Takahashi N, Goto M, Sunakawa Y, Kato T, Otsuka T, Abutani H, Tukachinsky H, Lee JK, Oxnard GR, Kuramoto N, Horasawa S, Sakamoto Y, Taniguchi H, Yoshino T. Benefits of Combining Circulating Tumor DNA With Tissue and Longitudinal Circulating Tumor DNA Genotyping in Advanced Solid Tumors: SCRUM-Japan MONSTAR-SCREEN-1 Study. JCO Precis Oncol 2025; 9:e2400283. [PMID: 40209142 PMCID: PMC12005867 DOI: 10.1200/po.24.00283] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 12/23/2024] [Accepted: 02/21/2025] [Indexed: 04/12/2025] Open
Abstract
PURPOSE The utility of capturing heterogeneity by circulating tumor DNA (ctDNA) genotyping combined with tissue analysis or applying it in a sequential manner remains uncertain. METHODS We assessed the clinical value of ctDNA genotyping using data from 2,187 patients with advanced solid tumors enrolled in SCRUM-Japan MONSTAR-SCREEN-1, a nationwide cancer genome screening project, which examined ctDNA from longitudinally collected blood samples and tumor tissue samples (UMIN 000036749). RESULTS Among 667 patients with both baseline ctDNA and tissue genotyping results, 51 (7.6%) had actionable biomarkers identified exclusively through ctDNA genotyping. The most frequent targets of genotype-matched therapy guided by solely ctDNA were immune checkpoint, estrogen receptor, and poly(ADP-ribose) polymerase (PARP). Comparison of objective response rates (ORRs) and progression-free survival (PFS) between patients treated based on tissue versus ctDNA alone showed no significant difference, with ORRs of 34.0% versus 23.1% (P = .54) and a median PFS of 11.5 versus 13.8 months (hazard ratio [HR], 1.4 [95% CI, 0.72 to 2.80]), respectively. Among 924 patients undergoing sequential ctDNA genotyping, the detection of actionable biomarkers increased from 63.2% to 72.5% following subsequent ctDNA. Targets for genotype-matched therapy guided by subsequent ctDNA alone commonly included PARP, immune checkpoint, and BRAF. The ORR was 23.2% and 26.7% (P = .75), and the median PFS was 5.2 and. 3.7 months (HR, 1.5 [95% CI, 0.79 to 2.80]) for genotype-matched therapy based on initial versus subsequent ctDNA alone, respectively. CONCLUSION Combining ctDNA with tissue analysis, followed by sequential ctDNA assessments, effectively enhances the identification of actionable biomarkers. This strategy facilitates clinically beneficial, genetically informed therapies, underscoring its significant value in precision oncology.
Collapse
Affiliation(s)
- Takao Fujisawa
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Course of Advanced Clinical Research of Cancer, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Yoshiaki Nakamura
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- International Research Promotion Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hideaki Bando
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Masafumi Ikeda
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Norio Nonomura
- Department of Urology, Osaka University Graduate School of Medicine, Suita, Japan
| | - Nobuaki Matsubara
- Department of Medical Oncology, National Cancer Center Hospital East, Chiba, Japan
| | - Hiroji Iwata
- Department of Breast Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Yoichi Naito
- Department of Medical Oncology, National Cancer Center Hospital East, Chiba, Japan
- Department of General Internal Medicine, National Cancer Center Hospital East, Chiba, Japan
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan
| | - Susumu Okano
- Department of Head and Neck Medical Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Daisuke Aoki
- Department of Obstetrics and Gynecology, Keio University School of Medicine, Tokyo, Japan
| | - Kenichi Harano
- Department of Medical Oncology, National Cancer Center Hospital East, Chiba, Japan
- Department of Experimental Therapeutics, National Cancer Center Hospital East, Chiba, Japan
| | - Naoya Yamazaki
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Kenjiro Namikawa
- Department of Dermatologic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Kanagawa Cancer Center, Yokohama, Japan
| | - Shigenori Kadowaki
- Department of Clinical Oncology, Aichi Cancer Center Hospital, Nagoya, Japan
| | - Eiji Oki
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshito Komatsu
- Department of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Taroh Satoh
- Center for Cancer Genomics and Precision Medicine, Osaka University Hospital, Suita, Japan
| | - Taito Esaki
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Tetsuya Hamaguchi
- Department of Gastroenterological Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shunto-gun, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery and Pediatric Surgery, Center for One Medicine Innovative Translational Research, Gifu University Graduate School of Medicine, Gifu, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Hironaga Satake
- Cancer Center, Kansai Medical University Hospital, Hirakata, Japan
- Department of Medical Oncology, Kochi Medical School, Kochi, Japan
| | - Tomohiro Nishina
- Department of Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Naoki Takahashi
- Department of Gastroenterology, Saitama Cancer Center, Kitaadachi-gun, Japan
| | - Masahiro Goto
- Cancer Chemotherapy Center, Osaka Medical and Pharmaceutical University Hospital, Takatsuki, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan
| | - Takeshi Kato
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Tomoyuki Otsuka
- Department of Medical Oncology, Osaka International Cancer Institute, Osaka, Japan
| | | | | | | | | | - Naomi Kuramoto
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Satoshi Horasawa
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Yasutoshi Sakamoto
- Translational Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiroya Taniguchi
- Department of Surgery and Science, Kyushu University, Fukuoka, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Department of the Promotion of Drug and Diagnostic Development, National Cancer Center Hospital East, Kashiwa, Japan
| |
Collapse
|
25
|
Mancini M, De Santis S, Monaldi C, Castagnetti F, Iezza M, Iurlo A, Cattaneo D, Galimberti S, Cerrano M, Capodanno I, Bonifacio M, Rossi M, Agostinelli C, Meggendorfer M, Haferlach T, Cavo M, Gugliotta G, Soverini S. SETD2 loss of function is a recurrent event in advanced-phase chronic myeloid leukemia and contributes to genomic instability: SETD2 loss in Chronic Myeloid Leukemia. Clin Transl Med 2025; 15:e70163. [PMID: 40275711 PMCID: PMC12022228 DOI: 10.1002/ctm2.70163] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2024] [Revised: 12/10/2024] [Accepted: 12/18/2024] [Indexed: 04/26/2025] Open
Abstract
The SETD2 tumour suppressor encodes a histone methyltransferase that specifically trimethylates histone H3 on lysine 36 (H3K36me3), a key histone mark implicated in the maintenance of genomic integrity among other functions. We found that SETD2 protein deficiency, mirrored by H3K36me3 deficiency, is a nearly universal event in advanced-phase chronic myeloid leukemia (CML) patients. Similarly, K562 and KCL22 cell lines exhibited markedly reduced or undetectable SETD2/H3K36me3 levels, respectively. This resulted from altered SETD2 protein turnover rather than mutations or transcriptional downregulation, and proteasome inhibition led to the accumulation of hyper-ubiquitinated SETD2 and to H3K36me3 rescue suggesting that a functional SETD2 protein is produced but abnormally degraded. We demonstrated that phosphorylation by Aurora-A kinase and ubiquitination by MDM2 plays a key role in the proteasome-mediated degradation of SETD2. Moreover, we found that SETD2 and H3K36me3 loss impinges on the activation and proficiency of homologous recombination and mismatch repair. Finally, we showed that proteasome and Aurora-A kinase inhibitors, acting via SETD2/H3K36me3 rescue, are effective in inducing apoptosis and reducing clonogenic growth in cell lines and primary cells from advanced-phase patients. Taken together, our results point to SETD2/H3K36me3 deficiency as a mechanism, already identified by our group in systemic mastocytosis, that is reversible, druggable, and BCR::ABL1-independent, able to cooperate with BCR::ABL1 in driving genetic instability in CML. KEY POINTS: Virtually all CML patients in blast crisis display SETD2 loss of function. SETD2 loss seems to be accomplished at the posttranslational level rather than being the result of genetic/genomic hits or transcriptional repression. Phosphorylation by Aurora kinase A and ubiquitination by MDM2 contribute to SETD2 proteasome-mediated degradation in blast crisis CML patients. Loss of SETD2 results in increased DNA damage.
Collapse
Affiliation(s)
- Manuela Mancini
- IRCCS Azienda Ospedaliero‐Universitaria di BolognaIstituto di Ematologia “Seràgnoli”BolognaItaly
| | - Sara De Santis
- Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly
| | - Cecilia Monaldi
- Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly
| | - Fausto Castagnetti
- Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly
| | - Miriam Iezza
- Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly
| | - Alessandra Iurlo
- Hematology DivisionFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanoItaly
| | - Daniele Cattaneo
- Hematology DivisionFoundation IRCCS Ca' Granda Ospedale Maggiore PoliclinicoMilanoItaly
- Department of Oncology and Hemato‐OncologyUniversity of MilanMilanoItaly
| | - Sara Galimberti
- Clinical and Experimental MedicineHematologyUniversity of PisaPisaItaly
| | - Marco Cerrano
- Azienda Ospedaliera Citta' Della Salute E Della Scienza Di TorinoTorinoItaly
| | | | - Massimiliano Bonifacio
- Section of HematologyDepartment of MedicineAzienda Ospedaliera Universitaria Integrata di VeronaVeronaItaly
| | - Maura Rossi
- IRCCS Azienda Ospedaliero‐Universitaria di BolognaIstituto di Ematologia “Seràgnoli”BolognaItaly
| | - Claudio Agostinelli
- IRCCS Azienda Ospedaliero‐Universitaria di BolognaIstituto di Ematologia “Seràgnoli”BolognaItaly
- Haematopathology UnitIRCCS Azienda Ospedaliero‐Universitaria di BolognaBolognaItaly
| | | | | | - Michele Cavo
- IRCCS Azienda Ospedaliero‐Universitaria di BolognaIstituto di Ematologia “Seràgnoli”BolognaItaly
| | - Gabriele Gugliotta
- IRCCS Azienda Ospedaliero‐Universitaria di BolognaIstituto di Ematologia “Seràgnoli”BolognaItaly
| | - Simona Soverini
- Department of Medical and Surgical SciencesUniversity of BolognaBolognaItaly
| |
Collapse
|
26
|
Woolley CE, Domingo E, Fernandez-Tajes J, Pennel KA, Roxburgh P, Edwards J, Richman SD, Maughan TS, Kerr DJ, Soriano I, Tomlinson IP. Coevolution of Atypical BRAF and KRAS Mutations in Colorectal Tumorigenesis. Mol Cancer Res 2025; 23:300-312. [PMID: 39751654 PMCID: PMC7617415 DOI: 10.1158/1541-7786.mcr-24-0464] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 11/13/2024] [Accepted: 12/30/2024] [Indexed: 01/04/2025]
Abstract
BRAF mutations in colorectal cancer comprise three functional classes: class 1 (V600E) with strong constitutive activation, class 2 with pathogenic kinase activity lower than that of class 1, and class 3 which paradoxically lacks kinase activity. Non-class 1 mutations associate with better prognosis, microsatellite stability, distal tumor location, and better anti-EGFR response. An analysis of 13 colorectal cancer cohorts (n = 6,605 tumors) compared class 1 (n = 709, 10.7% of colorectal cancers), class 2 (n = 31, 0.47%), and class 3 (n = 81, 1.22%) mutations. Class 2-mutant and class 3-mutant colorectal cancers frequently co-occurred with additional Ras pathway mutations (29.0% and 45.7%, respectively, vs. 2.40% in class 1; P < 0.001), often at atypical sites (KRAS noncodon 12/13/61, NRAS, or NF1). Ras pathway activation was highest in class 1 and lowest in class 3, with a greater distal expression of EGFR ligands (amphiregulin/epiregulin) supporting weaker BRAF driver mutations. Unlike class 1 mutants, class 3 tumors resembled chromosomally unstable colorectal cancers in mutation burdens, signatures, driver mutations, and transcriptional subtypes, whereas class 2 mutants displayed intermediate characteristics. Atypical BRAF mutations were associated with longer overall survival than class 1 mutations (HR = 0.25; P = 0.011) but lost this advantage in cancers with additional Ras mutations (HR = 0.94; P = 0.86). This study supports the suggestion that class 3 BRAF mutations amplify existing Ras signaling in a two-mutation model and that the enhancement of weak/atypical Ras mutations may suffice for tumorigenesis, with potentially clinically important heterogeneity in the class 2/3 subgroup. Implications: The heterogeneous nature of BRAF-mutant colorectal cancers, particularly among class 2/3 mutations which frequently harbor additional Ras mutations, highlights the necessity of comprehensive molecular profiling.
Collapse
Affiliation(s)
- Connor E. Woolley
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - Enric Domingo
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | | | - Kathryn A.F. Pennel
- School of Cancer Science, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Patricia Roxburgh
- School of Cancer Science, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Joanne Edwards
- School of Cancer Science, Wolfson Wohl Cancer Research Centre, University of Glasgow, Glasgow, United Kingdom
| | - Susan D. Richman
- Division of Pathology and Data Analytics, University of Leeds, Leeds, United Kingdom
| | - Tim S. Maughan
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | - David J. Kerr
- Radcliffe Department of Medicine, University of Oxford, Oxford, United Kingdom
| | - Ignacio Soriano
- Department of Oncology, University of Oxford, Oxford, United Kingdom
| | | |
Collapse
|
27
|
Takahashi Y, Horikawa Y, Matsuyama Y, Asai K, Endo J, Yabe D. A Novel Multiple Endocrine Neoplasia Type 1 Gene Variant Found in Scalp Pulmonary Neuroendocrine Tumor Metastasis. JCEM CASE REPORTS 2025; 3:luaf047. [PMID: 40115415 PMCID: PMC11924372 DOI: 10.1210/jcemcr/luaf047] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Indexed: 03/23/2025]
Abstract
Multiple endocrine neoplasia type 1 (MEN1) is a genetic disorder usually diagnosed following hyperparathyroidism or pancreatic and gastrointestinal neuroendocrine neoplasm (NEN). We report here a case of MEN1 that was diagnosed following cancer multigene panel testing of a scalp metastasis of small cell lung carcinoma (SCLC). A 45-year-old male had noticed weight loss 20 months before admission to our department. He was identified with multiple nodules in the lungs, and bronchoscopy permitted diagnosis of SCLC at another hospital. He was then relocated to our hospital, where he began receiving chemotherapy and radiation therapy. A metastatic lesion had appeared on his scalp 3 months before admission, which had been diagnosed as a neuroendocrine tumor (NET, corresponding to grade 2) based on histopathological examination. Cancer multigene panel testing was performed and a MEN1 variant (c.266T > G; p.Leu89Arg) was discovered; the patient was then referred to our department. Germline genetic testing revealed the same, novel germline variant in MEN1, leading to his diagnosis of MEN1 and lung NEN metastases. In this case, the stage of NENs can vary between the primary tumor (SCLC) and its metastases (NET), potentially involving second-hit mutations or tumor suppressor genes.
Collapse
Affiliation(s)
- Yoshihiro Takahashi
- Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
- Department of Clinical Genetics Center, Gifu University Hospital, Gifu 501-1194, Japan
| | - Yukio Horikawa
- Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
- Department of Clinical Genetics Center, Gifu University Hospital, Gifu 501-1194, Japan
| | - Yumi Matsuyama
- Department of Clinical Genetics Center, Gifu University Hospital, Gifu 501-1194, Japan
| | - Kimiko Asai
- Department of Clinical Genetics Center, Gifu University Hospital, Gifu 501-1194, Japan
| | - Junki Endo
- Department of Cardiology and Respiratory Medicine, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
| | - Daisuke Yabe
- Department of Diabetes, Endocrinology and Metabolism and Department of Rheumatology and Clinical Immunology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan
- Yutaka Seino Distinguished Center for Diabetes Research, Kansai Electric Power Medical Research Institute, Osaka 553-0003, Japan
- Center for One Medicine Innovative Translational Research, Gifu University, Gifu 501-1194, Japan
| |
Collapse
|
28
|
Ma J, Del Balzo L, Walch H, Khaleel S, Knezevic A, Flynn J, Zhang Z, Eichholz J, Doshi SD, Voss MH, Freeman B, Ari Hakimi A, Lee CH, Bale TA, Kelly D, Mueller BA, Mann J, Yu Y, Zinovoy M, Chen L, Cuaron J, Khan A, Yamada Y, Shin JY, Beal K, Moss NS, Carlo MI, Motzer RJ, Imber BS, Kotecha RR, Pike LRG. Clinical Outcomes and Targeted Genomic Analysis of Renal Cell Carcinoma Brain Metastases Treated with Stereotactic Radiosurgery. Eur Urol Oncol 2025; 8:338-346. [PMID: 39107179 DOI: 10.1016/j.euo.2024.07.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2023] [Revised: 06/28/2024] [Accepted: 07/09/2024] [Indexed: 08/09/2024]
Abstract
BACKGROUND Molecular profiles of renal cell carcinoma (RCC) brain metastases (BMs) are not well characterized. Effective management with locoregional therapies, including stereotactic radiosurgery (SRS), is critical as systemic therapy advancements have improved overall survival (OS). OBJECTIVE To identify clinicogenomic features of RCC BMs treated with SRS in a large patient cohort. DESIGN, SETTING, AND PARTICIPANTS A single-institution retrospective analysis was conducted of all RCC BM patients treated with SRS from January 1, 2010 to March 31, 2021. INTERVENTION SRS for RCC BMs. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Next-generation sequencing was performed to identify gene alterations more prevalent in BM patients. Clinical factors and genes altered in ≥10% of samples were assessed per patient using Cox proportional hazards models and per individual BM using clustered competing risks regression with competing risk of death. RESULTS AND LIMITATIONS Ninety-one RCC BM patients underwent SRS to 212 BMs, with a median follow-up of 38.8 mo for patients who survived. The median intracranial progression-free survival and OS were 7.8 (interquartile range [IQR] 5.7-11) and 21 (IQR 16-32) mo, respectively. Durable local control of 83% was achieved at 12 mo after SRS, and 59% of lesions initially meeting the radiographic criteria for progression at 3-mo evaluation would be considered to represent pseudoprogression at 6-mo evaluation. A comparison of genomic alterations at both the gene and the pathway level for BM+ patients compared with BM- patients revealed phosphoinositide 3-kinase (PI3K) pathway alterations to be more prevalent in BM+ patients (43% vs 16%, p = 0.001, q = 0.01), with the majority being PTEN alterations (17% vs 2.7%, p = 0.003, q = 0.041). CONCLUSIONS To our knowledge, this is the largest study investigating genomic profiles of RCC BMs and the only such study with annotated intracranial outcomes. SRS provides durable in-field local control of BMs. Recognizing post-SRS pseudoprogression is crucial to ensure appropriate management. The incidence of PI3K pathway alterations is more prevalent in BM+ patients than in BM- patients and warrants further investigation in a prospective setting. PATIENT SUMMARY We examined the outcomes of radiotherapy for the treatment of brain metastases in kidney cancer patients at a single large referral center. We found that radiation provides good control of brain tumors, and certain genetic mutations may be found more commonly in patients with brain metastasis.
Collapse
Affiliation(s)
- Jennifer Ma
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Luke Del Balzo
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Medical College of Georgia, Augusta, GA, USA
| | - Henry Walch
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sari Khaleel
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Andrea Knezevic
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jessica Flynn
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Zhigang Zhang
- Department of Epidemiology-Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jordan Eichholz
- Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sahil D Doshi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Martin H Voss
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Benjamin Freeman
- Department of Surgical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - A Ari Hakimi
- Department of Surgical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Chung-Han Lee
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Tejus A Bale
- Department of Molecular Diagnostics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Daniel Kelly
- Technology Division, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Boris A Mueller
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Justin Mann
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yao Yu
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Melissa Zinovoy
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Linda Chen
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - John Cuaron
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Atif Khan
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Yoshiya Yamada
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jacob Y Shin
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kathryn Beal
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nelson S Moss
- Department of Neurosurgery and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria I Carlo
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Robert J Motzer
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Brandon S Imber
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ritesh R Kotecha
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Luke R G Pike
- Department of Radiation Oncology and Brain Metastasis Center, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| |
Collapse
|
29
|
Tao JJ, Setton J, Sánchez Vela P, Safonov AM, Comen EA, Braunstein LZ, Reis-Filho JS, Riaz N, Powell SN, Levine RL, Norton L, Razavi P, Khan AJ. Impact of Clonal Hematopoiesis on Solid Tumor Progression Following Radiation Therapy. JCO Precis Oncol 2025; 9:e2400548. [PMID: 40249883 DOI: 10.1200/po-24-00548] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Revised: 09/30/2024] [Accepted: 01/07/2025] [Indexed: 04/20/2025] Open
Abstract
PURPOSE Clonal hematopoiesis (CH) has been shown to adversely affect outcomes in patients with nonhematologic cancers. However, the effects of CH on response to specific treatments, including radiation therapy (RT), are unknown. METHODS We analyzed patients with solid tumors harboring nonpathogenic somatic or germline ATM mutations (n = 144) and FAT1 mutations (n = 270) who received RT and underwent prospective tumor and matched WBC sequencing using the Memorial Sloan Kettering Integrated Mutation Profiling of Actionable Cancer Targets assay. CH variants were detected in blood samples using a well-validated CH variant detection pipeline. We compared irradiated tumor progression in patients with and without CH. Nonpathogenic ATM mutations and FAT1 mutations have previously been shown not to be associated with response to RT. RESULTS The final cohort consisted of 412 patients who underwent 811 total courses of RT. One hundred sixty-one patients (39.1%) had CH; the most frequently mutated genes were DNMT3A (25.6%), PPM1D (6.2%), TET2 (5.8%), and TP53 (5.0%). Fine-Gray competing-risks analysis, with death treated as a competing event, showed no difference in irradiated tumor progression between patients with and without CH (hazard ratio, 1.09 [95% CI, 0.72 to 1.66]; P = .68). Similarly, subanalyses of CH variant allele frequency and CH mutations in putative cancer drivers did not reveal an association with RT response. CONCLUSION We found no difference in irradiated tumor progression between patients with and without CH. Further studies are warranted to examine the potential clinical implications of CH on treatment responsiveness of solid tumors.
Collapse
Affiliation(s)
| | - Jeremy Setton
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Pablo Sánchez Vela
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Anton M Safonov
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Elizabeth A Comen
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Lior Z Braunstein
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Jorge S Reis-Filho
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Nadeem Riaz
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Simon N Powell
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Ross L Levine
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Larry Norton
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Pedram Razavi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY
| | - Atif J Khan
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY
| |
Collapse
|
30
|
Exarchos A, Bourla AB, Kaur M, Schulze K, Maund S, Cao Y, Zhao Y, Williams EH, Gaffey SC, Zuniga R, Lakhanpal S, Antic V, Doral M, Sy J, Meropol NJ, Chiang AC. Real-world enrollment for a prospective clinico-genomic database using a pragmatic technology-enabled platform. Contemp Clin Trials Commun 2025; 44:101446. [PMID: 40027276 PMCID: PMC11869879 DOI: 10.1016/j.conctc.2025.101446] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 10/15/2024] [Accepted: 02/01/2025] [Indexed: 03/05/2025] Open
Abstract
Background Discovery and incorporation of predictive and prognostic biomarkers enhance outcomes for patients with cancer. Clinico-genomic datasets, which retrospectively link real-world clinical data to tumor sequencing data, are important resources for biomarker research, which has historically relied on robust research infrastructures exclusive to large academic centers. The objective was to evaluate the feasibility of a pragmatic, technology-enabled platform at community-based research sites for development of a prospective clinico-genomic database supported by centralized electronic health record (EHR)-based patient ascertainment and data processing. Methods Adults with stage IV or recurrent metastatic non-small cell lung cancer or extensive-stage small-cell lung cancer were enrolled at 23 US sites upon initiating a standard line of therapy. Enrollment rates were estimated from eligible populations at individual centers. Clinical data from routinely collected EHR documentation were centrally processed and normalized for quality control. Serial blood samples at pre-specified timepoints (baseline, during treatment and at disease progression/end of therapy) were used for circulating tumor DNA (ctDNA) genomic profiling. Results Between December 2019 and May 2021, 944 patients enrolled, representing ≈25 % of eligible patients. Eight-hundred seventeen of 944 (87 %), 406 of 606 (67 %) and 398 of 852 (47 %) participants provided qualifying samples for ctDNA testing at baseline, during treatment and at disease progression/end of therapy, respectively. Samples were provided at all three timepoints by 35 % of participants. Conclusion A community-based oncology patient cohort was rapidly enrolled, creating a real-world clinico-genomic dataset. This pragmatic study platform has potential research applications where prospective real-world data may contribute to evidence generation.
Collapse
Affiliation(s)
| | | | | | | | | | - Yi Cao
- Genentech, Inc., South San Francisco, CA, USA
| | - Yihua Zhao
- Flatiron Health, Inc., New York, NY, USA
| | | | | | | | | | | | | | - Johanna Sy
- Genentech, Inc., South San Francisco, CA, USA
| | | | | |
Collapse
|
31
|
Chang MJ, Stamos DB, Urtis C, Bowers NL, Schmalz LM, Deyo LJ, Porebski MF, Jabir AR, Bunch PM, Lycan TW, Buchanan Doerfler L, Patwa HS, Waltonen JD, Sullivan CA, Browne JD, Zhang W, Porosnicu M. Mutational Profile of Blood and Tumor Tissue and Biomarkers of Response to PD-1 Inhibitors in Patients with Cutaneous Squamous Cell Carcinoma. Cancers (Basel) 2025; 17:1172. [PMID: 40227722 PMCID: PMC11987913 DOI: 10.3390/cancers17071172] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2025] [Revised: 03/14/2025] [Accepted: 03/25/2025] [Indexed: 04/15/2025] Open
Abstract
BACKGROUND/OBJECTIVES Cutaneous squamous cell carcinoma (cSCC) harbors one of the most mutated genomes. There are limited data on the genomic profile and its predictive potential for response to immunotherapy with PD-1 inhibitors in cSCC. METHODS This study retrospectively reviewed cSCC patients treated with PD-1 inhibitor monotherapy at a single institution. Clinical characteristics, treatment outcomes, PD-L1 expression, tumor mutation burden (TMB), and genomic profile in tumor and blood were analyzed. Logistic regression and a support vector classifier were used to validate identified biomarkers of significance. RESULTS Twenty-five patients were evaluable for response and had genomics tested in tumor and/or blood. Of the total, 80% of patients achieved an objective response: 40% complete response (CR), 32% partial response (PR) for more than 6 months, and 8% stable disease (SD) for more than 1 year; 20% of patients progressed on treatment. With a median follow-up of 21 months, progression-free survival (PFS) was 28 months in responders vs. 3 months in non-responders (p = 0.00001). Median PD-L1 was 25% in responders vs. 10% in non-responders (p = 0.39). There was no difference in median TMB between responders and non-responders. Eight gene mutations were significantly more frequent in non-responders than in responders: CDK12 (p = 0.005), CTCF (p = 0.033), CTNNB1 (p = 0.033), IGF1R (p = 0.038), IKBKE (p = 0.016), MLH1 (0.033), QKI (p = 0.016), and TIPARP (p = 0.033). A support vector model of these genes classified responders and non-responders with an accuracy of 0.88 in the training data and 1.0 in the testing data. CONCLUSIONS PD-1 inhibitor monotherapy produces an impressive response. Eight gene mutations were significantly more frequent in non-responders. PD-L1 and TMB were inconclusive in predicting treatment response to anti-PD-L1.
Collapse
Affiliation(s)
- Mark J. Chang
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (M.J.C.); (D.B.S.); (L.J.D.); (M.F.P.); (A.R.J.); (T.W.L.J.)
| | - Daniel B. Stamos
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (M.J.C.); (D.B.S.); (L.J.D.); (M.F.P.); (A.R.J.); (T.W.L.J.)
| | - Cetin Urtis
- Center for Cancer Genomics and Precision Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (C.U.); (L.M.S.); (W.Z.)
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
| | | | - Lauren M. Schmalz
- Center for Cancer Genomics and Precision Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (C.U.); (L.M.S.); (W.Z.)
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
| | - Logan J. Deyo
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (M.J.C.); (D.B.S.); (L.J.D.); (M.F.P.); (A.R.J.); (T.W.L.J.)
| | - Martin F. Porebski
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (M.J.C.); (D.B.S.); (L.J.D.); (M.F.P.); (A.R.J.); (T.W.L.J.)
| | - Abdur Rahman Jabir
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (M.J.C.); (D.B.S.); (L.J.D.); (M.F.P.); (A.R.J.); (T.W.L.J.)
| | - Paul M. Bunch
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
- Department of Radiology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Thomas W. Lycan
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (M.J.C.); (D.B.S.); (L.J.D.); (M.F.P.); (A.R.J.); (T.W.L.J.)
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
| | - Laura Buchanan Doerfler
- Department of Dermatology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA;
| | - Hafiz S. Patwa
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
- Department of Otolaryngology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Joshua D. Waltonen
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
- Department of Otolaryngology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Christopher A. Sullivan
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
- Department of Otolaryngology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - J. Dale Browne
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
- Department of Otolaryngology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA
| | - Wei Zhang
- Center for Cancer Genomics and Precision Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (C.U.); (L.M.S.); (W.Z.)
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
| | - Mercedes Porosnicu
- Department of Internal Medicine, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA; (M.J.C.); (D.B.S.); (L.J.D.); (M.F.P.); (A.R.J.); (T.W.L.J.)
- Wake Forest Baptist Comprehensive Cancer Center, Winston-Salem, NC 27157, USA (H.S.P.); (J.D.W.); (C.A.S.); (J.D.B.)
| |
Collapse
|
32
|
Gallagher P, Rolfo C, Elez E, Taieb J, Houlden J, Collins L, Roberts C, André T, Lawler M, Di Nicolantonio F, Grayson M, Boyd R, Popovici V, Bardelli A, Carson R, Khawaja H, Laurent-Puig P, Salto-Tellez M, Hennessy BT, Maughan TS, Tabernero J, Adams R, Jones R, Peeters M, Middleton MR, Wilson RH, Van Schaeybroeck S. A phase Ia study of the MEK1/2 inhibitor PD-0325901 with the c-MET inhibitor crizotinib in patients with advanced solid cancers. BJC REPORTS 2025; 3:17. [PMID: 40140597 PMCID: PMC11947101 DOI: 10.1038/s44276-025-00133-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/08/2025] [Revised: 03/04/2025] [Accepted: 03/08/2025] [Indexed: 03/28/2025]
Abstract
BACKGROUND Single-agent MEK1/2 inhibition has been disappointing in clinical trials targeting RAS mutant (MT) cancers, probably due to upstream receptor activation, resulting in resistance. We previously found that dual c-MET/MEK1/2 inhibition attenuated RASMT colorectal cancer (CRC) xenograft growth. In this study, we assessed safety of MEK1/2 inhibitor PD-0325901 with c-MET inhibitor crizotinib and determined the optimal biological doses for subsequent clinical trials. METHODS In this dose-escalation phase I trial, patients with advanced solid tumours received PD-0325901 with crizotinib, using a rolling-6 design to determine the maximum tolerable dose (MTD) and safety/tolerability. Blood samples for pharmacokinetics and skin biopsies were collected. RESULTS Twenty-five patients were recruited in 4 cohorts up to doses of crizotinib 200 mg B.D continuously with PD-0325901 8 mg B.D, days 1-21 every 28 days. One in six patients exhibited a dose-limiting toxicity at this dose level. Drug-related adverse events were in keeping with single-agent toxicity profiles. The best clinical response was stable disease in seven patients (29%). CONCLUSIONS PD-0325901/crizotinib can be given together at pharmacologically-active doses. The MTD for PD-0325901/crizotinib was 8 mg B.D (days 1-21) and 200 mg B.D continuously in a 28-days cycle. The combination was further explored with an alternate MEK1/2 inhibitor in RASMT CRC patients. EUDRACT-NUMBER 2014-000463-40.
Collapse
Affiliation(s)
- Peter Gallagher
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Christian Rolfo
- Department of Medical Oncology, University of Antwerp/Antwerp University Hospital, Wilrijk, Belgium
| | - Elena Elez
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain
| | - Julien Taieb
- Department of GI Oncology Hôpital Européen Georges-Pompidou, Institut du cancer Paris Carpem, AP-HP, Université Paris Cité, Paris, France
| | - Jennifer Houlden
- Department of Oncology, Oncology Clinical Trials Office (OCTO), University of Oxford, Oxford, UK
| | - Linda Collins
- Department of Oncology, Oncology Clinical Trials Office (OCTO), University of Oxford, Oxford, UK
| | - Corran Roberts
- Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, Centre for Statistics in Medicine, University of Oxford, Oxford, UK
| | - Thierry André
- Department of Medical Oncology, Sorbonne Université, Hôpital Saint Antoine, Paris, France
| | - Mark Lawler
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | | | - Margaret Grayson
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK
| | - Ruth Boyd
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK
| | - Vlad Popovici
- RECETOX, Faculty of Science, Masaryk University, Brno, Czech Republic
| | - Alberto Bardelli
- Department of Oncology, Molecular Biotechnology Center, University of Torino, Torino, Italy
- IFOM ETS, The AIRC Institute of Molecular Oncology, Milano, Italy
| | - Robbie Carson
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Hajrah Khawaja
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Pierre Laurent-Puig
- Centre de recherche des cordeliers, INSERM, Sorbonne Université, Université Paris Cité, Paris, France
| | - Manuel Salto-Tellez
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Bryan T Hennessy
- Royal College of Surgeons in Ireland University of Medicine and Health Sciences, Dublin, Ireland
| | - Tim S Maughan
- Department of Oncology, Old Road Campus Research Building Roosevelt Drive, University of Oxford, Oxford, UK
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Ashton St, Liverpool, UK
| | - Josep Tabernero
- Vall d'Hebron University Hospital and Institute of Oncology (VHIO), Barcelona, Spain
| | - Richard Adams
- Cardiff University and Velindre University NHS Trust, Cardiff, UK
| | - Robert Jones
- Cardiff University and Velindre University NHS Trust, Cardiff, UK
| | - Marc Peeters
- Department of Medical Oncology, University of Antwerp/Antwerp University Hospital, Wilrijk, Belgium
| | - Mark R Middleton
- Department of Oncology, Old Road Campus Research Building Roosevelt Drive, University of Oxford, Oxford, UK
| | - Richard H Wilson
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK
| | - Sandra Van Schaeybroeck
- Northern Ireland Cancer Centre, Belfast Health and Social Care Trust, Belfast, UK.
- Patrick G. Johnston Centre for Cancer Research, School of Medicine, Dentistry and Biomedical Science, Queen's University Belfast, Belfast, UK.
| |
Collapse
|
33
|
Boos LA, Doerig C, Gut G, Miglino N, Fábregas Ibáñez L, Rizzo S, Schärfe Fruechtenicht C, Chitale N, Lu C, Zoche M, Bodenmiller B, Chevrier S, Eklund AS, Nowak M, Rahmani Khajouei S, Berardo CG, Kaczmarek L, Bosshard K, Archey W, Bodmer M, Glinz D, Camarillo-Retamosa E, Hempel CL, Rahimzadeh P, Gosztonyi B, Richter U, Bankel L, Wicki A. Precision Oncology Program (POP), an observational study using real-world data and imaging mass cytometry to explore decision support for the Molecular Tumor Board: study protocol. BMJ Open 2025; 15:e096591. [PMID: 40139698 PMCID: PMC11950961 DOI: 10.1136/bmjopen-2024-096591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/14/2024] [Accepted: 03/12/2025] [Indexed: 03/29/2025] Open
Abstract
INTRODUCTION Precision oncology aims to provide individualised treatment recommendations based on patient-specific characteristics. In this rapidly evolving field with increasing numbers of biomarkers and potential therapeutic targets, there is a growing unmet need for evidence guiding these individualised treatment recommendations. The Precision Oncology Program (POP) harnesses real-world data (RWD) and imaging mass cytometry (IMC) to evaluate the feasibility and utility of integrating different data modalities to inform personalised treatment recommendations. This program uses patient-matched clinicogenomic data and spatial single-cell proteomics analysis to support profiling-driven decision-making for patients with cancer at the Molecular Tumor Board. METHODS AND ANALYSIS The collaborative POP project recruits patients across all tumour entities and stages at the Comprehensive Cancer Center Zurich (CCCZ). For patients in the POP, a clinically and molecularly matched cohort is identified within the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinicogenomic database (CGDB). It assesses whether clinical, genomic and outcome data of the CGDB cohort can inform treatment recommendations. In addition, multiplexed imaging mass cytometry (IMC) is performed in formalin-fixed paraffin-embedded tissue to assess the potential impact of spatial proteomics on personalised treatment decisions. RWD and IMC information is reviewed in the Molecular Tumor Board to assess the potential impact of this information on therapy decisions. However, since this is an observational study, these additional recommendations remain nonprescriptive and will not be forwarded to the treating physician. ETHICS AND DISSEMINATION The study is registered at ClinicalTrials.gov (NCT06680726) and approved by the Canton of Zurich Ethics Committee (Project ID: 2022-02289). Project-specific informed consent is obtained from all participants. Deceased patients may also be included. In this case, a signed general consent form must be available. Data privacy is ensured by unique patient numbers for pseudo-anonymised data. Study findings will be disseminated through international peer-reviewed journals, conferences, and direct communication with participants and relevant organisations. TRIAL REGISTRATION NUMBER NCT06680726.
Collapse
Affiliation(s)
- Laura Amanda Boos
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
| | | | - Gabriele Gut
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Nicola Miglino
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Luis Fábregas Ibáñez
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Shemra Rizzo
- Personalized Healthcare Data Science, Genentech Inc, South San Francisco, California, USA
| | | | | | - Charles Lu
- Personalized Healthcare Data Science, Genentech Inc, South San Francisco, California, USA
| | - Martin Zoche
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Bernd Bodenmiller
- Department of Quantitative Biomedicine, University of Zurich, Zurich, Switzerland
| | | | | | - Marta Nowak
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | - Sepehr Rahmani Khajouei
- Department of Pathology and Molecular Pathology, University Hospital Zurich, Zurich, Switzerland
| | | | | | | | | | | | | | - Eva Camarillo-Retamosa
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Chiara Louisa Hempel
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
| | | | | | - Ulrich Richter
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
| | - Lorenz Bankel
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
| | - Andreas Wicki
- Department of Medical Oncology and Hematology, University Hospital Zurich, Zurich, Switzerland
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| |
Collapse
|
34
|
Babatunde OO, Coca Membribes S, Anthonescu C, Bradic M, O'Malley B, Linkov I, Bartlett E, Momtaz P, Alektiar K, Gounder MM, Rosenbaum E, Tap WD, D'Angelo SP, Kelly CM. Immunologic correlates in a CIC::DUX4 fusion-positive sarcoma responsive to dual immune checkpoint blockade. NPJ Precis Oncol 2025; 9:85. [PMID: 40128305 PMCID: PMC11933392 DOI: 10.1038/s41698-025-00878-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2024] [Accepted: 03/13/2025] [Indexed: 03/26/2025] Open
Abstract
CIC::DUX4 sarcoma (CDS) is a rare and aggressive subtype of soft tissue sarcoma with poor prognosis and limited treatment options. Immunotherapy has not been studied in this disease. To our knowledge, response to immune checkpoint blockade (ICB) has not been previously reported. Here, we present the first case of a patient with CDS responding to dual ICB with nivolumab and relatlimab. Immunohistochemical (IHC) analysis of pre-treatment samples revealed minimal immune cell infiltration, with scarce CD3+, CD8+, and FOXP3+ T-cells and negligible expression of PD-L1 and PD-1 markers. Post-treatment tumor samples revealed a significant shift in the immune microenvironment, with increased CD8 + T-cell infiltration and co-expression of exhaustion markers PD-1 and LAG-3 following treatment. These findings suggest that doublet ICB can activate an antitumor immune response in CDS, overcoming the immune cold phenotype typically associated with this sarcoma. This case provides the first evidence of dual PD-1/LAG-3 blockade inducing an immune response in CDS. The favorable response and tolerability observed in this patient highlight the potential of dual ICB as a therapeutic option in CDS that merits further investigation.
Collapse
Affiliation(s)
- Olayode O Babatunde
- Medical Oncology/Hematology Fellowship Program, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | | | - Cristina Anthonescu
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Martina Bradic
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Bernard O'Malley
- Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Irina Linkov
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Edmund Bartlett
- Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Parisa Momtaz
- Melanoma Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Kaled Alektiar
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mrinal M Gounder
- Sarcoma Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Evan Rosenbaum
- Sarcoma Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - William D Tap
- Sarcoma Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Sandra P D'Angelo
- Sarcoma Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Ciara M Kelly
- Sarcoma Medical Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
- Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| |
Collapse
|
35
|
Ma J, Daou R, Bou Eid J, Fregonese B, El-Khoury J, Wijetunga NA, Imber BS, Yahalom J, Hajj C. Management approaches for primary hepatic lymphoma: 10 year institutional experience with comprehensive literature review. Front Oncol 2025; 15:1475118. [PMID: 40182049 PMCID: PMC11965623 DOI: 10.3389/fonc.2025.1475118] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2024] [Accepted: 01/28/2025] [Indexed: 04/05/2025] Open
Abstract
Purpose/objective Primary hepatic lymphomas (PHL) are an extremely rare form of non-Hodgkin Lymphoma (NHL) for which there are no established treatment guidelines, with available literature largely comprised of small case reports. Therefore, we evaluate our institutional experience treating PHL within the context of existing literature to better understand treatment modalities, role of radiotherapy (RT), and outcomes. Materials/methods We conducted a single institutional retrospective study of all patients with PHL diagnosed from 2000-2021, defined as a biopsy-proven liver lesion in the absence of other lymphomatous solid organ involvement, except for concurrently diagnosed hepatosplenic lymphomas. Subgroup analysis was performed for diffuse large B-cell lymphoma (DLBCL) and indolent lymphomas, which included marginal zone lymphoma (MZL), Grade 1-2 follicular lymphoma (FL), and low-grade B-cell lymphoma (BCL), NOS. Univariable (UVA) and multivariable analysis (MVA) for overall survival (OS) were performed using the Cox proportional hazards model. A literature review was conducted using key words "liver", "lymphoma", and "treatment" to identify relevant literature. Results We identified 30 patients with PHL within the institutional cohort and 192 patients from comprehensive literature review. Subgroup analysis of DLBCL included 15 patients. On MVA for OS, only ECOG score (p=0.02) and Lugano stage (p=0.04) remained significant. Subgroup analysis of the indolent lymphoma group included 9 patients. On MVA for OS, only age remained significant. Systemic therapy was the most common treatment modality overall (20 patients; 67%) with surgery, radiation and observation utilized in 4 patients (13%) each. Seventeen (57%) of patients were alive at the time of data collection, with 8 (27%) deceased and 5 (17%) lost to follow-up. Conclusion PHL are an extremely rare subtype of NHL for which there is no clear treatment consensus. Primary hepatic DLBCL appears to be treated mostly with chemotherapy with good disease control. For indolent PHL, low-dose RT appears to have good overall disease control with minimal toxicity. Our RT data is limited by the short duration of follow-up for patients receiving RT compared to those who received chemotherapy, surgery or observation. However, our results are encouraging for the use of RT for appropriate patients with indolent PHL.
Collapse
Affiliation(s)
- Jennifer Ma
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Remy Daou
- Department of Family Medicine, Saint Joseph University, Beirut, Lebanon
| | - Josiane Bou Eid
- Department of Family Medicine, Saint Joseph University, Beirut, Lebanon
| | - Beatrice Fregonese
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Joe El-Khoury
- Department of Family Medicine, Saint Joseph University, Beirut, Lebanon
| | - N. Ari Wijetunga
- Department of Radiation Oncology, University of North Carolina (UNC) School of Medicine, Chapel Hill, NC, United States
| | - Brandon S. Imber
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Joachim Yahalom
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
| | - Carla Hajj
- Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, United States
- Department of Radiation Oncology, Cleveland Clinic, Abu Dhabi, United Arab Emirates
| |
Collapse
|
36
|
Tang K, Zhou L, Tian X, Fang SY, Vandenbulcke E, Du A, Shen J, Cao H, Zhou J, Chen K, Kim HR, Luo Z, Xin S, Lin SH, Park D, Yang L, Zhang Y, Suzuki K, Majety M, Ling X, Lam SZ, Chow RD, Ren P, Tao B, Li K, Codina A, Dai X, Shang X, Bai S, Nottoli T, Levchenko A, Booth CJ, Liu C, Fan R, Dong MB, Zhou X, Chen S. Cas12a-knock-in mice for multiplexed genome editing, disease modelling and immune-cell engineering. Nat Biomed Eng 2025:10.1038/s41551-025-01371-2. [PMID: 40114032 DOI: 10.1038/s41551-025-01371-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2024] [Accepted: 02/13/2025] [Indexed: 03/22/2025]
Abstract
The pleiotropic effects of human disease and the complex nature of gene-interaction networks require knock-in mice allowing for multiplexed gene perturbations. Here we describe a series of knock-in mice with a C57BL/6 background and with the conditional or constitutive expression of LbCas12a or of high-fidelity enhanced AsCas12a, which were inserted at the Rosa26 locus. The constitutive expression of Cas12a in the mice did not lead to discernible pathology and enabled efficient multiplexed genome engineering. We used the mice for the retrovirus-based immune-cell engineering of CD4+ and CD8+ T cells, B cells and bone-marrow-derived dendritic cells, for autochthonous cancer modelling through the delivery of multiple CRISPR RNAs as a single array using adeno-associated viruses, and for the targeted genome editing of liver tissue using lipid nanoparticles. We also describe a system for simultaneous dual-gene activation and knockout (DAKO). The Cas12a-knock-in mice and the viral and non-viral delivery vehicles provide a versatile toolkit for ex vivo and in vivo applications in genome editing, disease modelling and immune-cell engineering, and for the deconvolution of complex gene interactions.
Collapse
Affiliation(s)
- Kaiyuan Tang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA
- Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA
| | - Liqun Zhou
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA
- Immunobiology Program, Yale University, New Haven, CT, USA
| | - Xiaolong Tian
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Shao-Yu Fang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
| | - Erica Vandenbulcke
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Yale College, Yale University, New Haven, CT, USA
| | - Andrew Du
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Yale College, Yale University, New Haven, CT, USA
| | - Johanna Shen
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Yale College, Yale University, New Haven, CT, USA
| | - Hanbing Cao
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
| | - Jerry Zhou
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Yale College, Yale University, New Haven, CT, USA
| | - Krista Chen
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Yale College, Yale University, New Haven, CT, USA
| | - Hyunu R Kim
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
| | - Zhicheng Luo
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA
| | - Shan Xin
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
| | - Shawn H Lin
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA
- Immunobiology Program, Yale University, New Haven, CT, USA
| | - Daniel Park
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Yale College, Yale University, New Haven, CT, USA
| | - Luojia Yang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA
- Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA
| | - Yueqi Zhang
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
| | - Kazushi Suzuki
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
| | - Medha Majety
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Yale College, Yale University, New Haven, CT, USA
| | - Xinyu Ling
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
| | - Stanley Z Lam
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Yale College, Yale University, New Haven, CT, USA
| | - Ryan D Chow
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- M.D.-Ph.D. Program, Yale University, West Haven, CT, USA
| | - Ping Ren
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
| | - Bo Tao
- System Biology Institute, Yale University, West Haven, CT, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Keyi Li
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA
| | - Adan Codina
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA
- Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA
| | - Xiaoyun Dai
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA
- System Biology Institute, Yale University, West Haven, CT, USA
- Center for Genome Editing, Westlake Laboratory of Life Sciences and Biomedicine, School of Medicine, Westlake University, Hangzhou, China
| | - Xingbo Shang
- System Biology Institute, Yale University, West Haven, CT, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
| | - Suxia Bai
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Timothy Nottoli
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Andre Levchenko
- System Biology Institute, Yale University, West Haven, CT, USA
- Immunobiology Program, Yale University, New Haven, CT, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA
| | - Carmen J Booth
- Department of Comparative Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Chen Liu
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
| | - Rong Fan
- System Biology Institute, Yale University, West Haven, CT, USA
- Department of Biomedical Engineering, Yale University, New Haven, CT, USA
- Department of Pathology, Yale University School of Medicine, New Haven, CT, USA
- Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA
- Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA
- Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA
| | - Matthew B Dong
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
- System Biology Institute, Yale University, West Haven, CT, USA.
- M.D.-Ph.D. Program, Yale University, West Haven, CT, USA.
- Department of Medicine, Johns Hopkins Hospital, Baltimore, MD, USA.
| | - Xiaoyu Zhou
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
- System Biology Institute, Yale University, West Haven, CT, USA.
| | - Sidi Chen
- Department of Genetics, Yale University School of Medicine, New Haven, CT, USA.
- System Biology Institute, Yale University, West Haven, CT, USA.
- Combined Program in the Biological and Biomedical Sciences, Yale University, New Haven, CT, USA.
- Molecular Cell Biology, Genetics, and Development Program, Yale University, New Haven, CT, USA.
- Immunobiology Program, Yale University, New Haven, CT, USA.
- Yale College, Yale University, New Haven, CT, USA.
- M.D.-Ph.D. Program, Yale University, West Haven, CT, USA.
- Department of Neurosurgery, Yale University School of Medicine, New Haven, CT, USA.
- Yale Comprehensive Cancer Center, Yale University School of Medicine, New Haven, CT, USA.
- Yale Stem Cell Center, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for RNA Science and Medicine, Yale University School of Medicine, New Haven, CT, USA.
- Yale Liver Center, Yale University School of Medicine, New Haven, CT, USA.
- Yale Center for Biomedical Data Science, Yale University School of Medicine, New Haven, CT, USA.
| |
Collapse
|
37
|
Vicario R, Fragkogianni S, Weber L, Lazarov T, Hu Y, Hayashi SY, Craddock B, Socci ND, Alberdi A, Baako A, Ay O, Ogishi M, Lopez-Rodrigo E, Kappagantula R, Viale A, Iacobuzio-Donahue CA, Zhou T, Ransohoff RM, Chesworth R, Abdel-Wahab O, Boisson B, Elemento O, Casanova JL, Miller WT, Geissmann F. A microglia clonal inflammatory disorder in Alzheimer's disease. eLife 2025; 13:RP96519. [PMID: 40085681 PMCID: PMC11908784 DOI: 10.7554/elife.96519] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/16/2025] Open
Abstract
Somatic genetic heterogeneity resulting from post-zygotic DNA mutations is widespread in human tissues and can cause diseases, however, few studies have investigated its role in neurodegenerative processes such as Alzheimer's disease (AD). Here, we report the selective enrichment of microglia clones carrying pathogenic variants, that are not present in neuronal, glia/stromal cells, or blood, from patients with AD in comparison to age-matched controls. Notably, microglia-specific AD-associated variants preferentially target the MAPK pathway, including recurrent CBL ring-domain mutations. These variants activate ERK and drive a microglia transcriptional program characterized by a strong neuro-inflammatory response, both in vitro and in patients. Although the natural history of AD-associated microglial clones is difficult to establish in humans, microglial expression of a MAPK pathway activating variant was previously shown to cause neurodegeneration in mice, suggesting that AD-associated neuroinflammatory microglial clones may contribute to the neurodegenerative process in patients.
Collapse
Affiliation(s)
- Rocio Vicario
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Stamatina Fragkogianni
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Leslie Weber
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Tomi Lazarov
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Yang Hu
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell New YorkNew YorkUnited States
| | - Samantha Y Hayashi
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony BrookNew YorkUnited States
| | - Barbara Craddock
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony BrookNew YorkUnited States
| | - Nicholas D Socci
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Araitz Alberdi
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Ann Baako
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Oyku Ay
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Masato Ogishi
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New YorkNew YorkUnited States
| | - Estibaliz Lopez-Rodrigo
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Rajya Kappagantula
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Agnes Viale
- Marie-Josée & Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Christine A Iacobuzio-Donahue
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Ting Zhou
- SKI Stem Cell Research Core, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | | | | | | | - Omar Abdel-Wahab
- Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| | - Bertrand Boisson
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New YorkNew YorkUnited States
| | - Olivier Elemento
- Department of Physiology and Biophysics, Institute for Computational Biomedicine, Weill Cornell New YorkNew YorkUnited States
| | - Jean-Laurent Casanova
- St. Giles Laboratory of Human Genetics of Infectious Diseases, Rockefeller Branch, The Rockefeller University, New YorkNew YorkUnited States
| | - W Todd Miller
- Department of Physiology and Biophysics, Stony Brook University School of Medicine, Stony BrookNew YorkUnited States
| | - Frédéric Geissmann
- Immunology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New YorkNew YorkUnited States
| |
Collapse
|
38
|
Perks CM, Barker RM, Alhadrami M, Alkahtani O, Gill E, Grishaw M, Harland AJ, Henley P, Li H, O’Sullivan E, Stone G, Su X, Kehoe PG. Curious Dichotomies of Apolipoprotein E Function in Alzheimer's Disease and Cancer-One Explanatory Mechanism of Inverse Disease Associations? Genes (Basel) 2025; 16:331. [PMID: 40149482 PMCID: PMC11942319 DOI: 10.3390/genes16030331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2025] [Revised: 03/05/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025] Open
Abstract
An apparent "inverse" relationship exists between two seemingly unconnected conditions, Alzheimer's disease (AD) and cancer, despite sharing similar risk factors, like increased age and obesity. AD is associated with amyloid beta (Aβ) plaques and neurofibrillary tau tangles that cause neural degeneration; cancer, in contrast, is characterized by enhanced cell survival and proliferation. Apolipoprotein E (ApoE) is the main lipoprotein found in the central nervous system and via its high affinity with lipoprotein receptors plays a critical role in cholesterol transport and uptake. ApoE has 3 protein isoforms, ApoE E2, ApoE E3, and ApoE E4, respectively encoded for by 3 allelic variants of APOE (ε2, ε3, and ε4). This review examines the characteristics and function of ApoE described in both AD and cancer to assimilate evidence for its potential contribution to mechanisms that may underly the reported inverse association between the two conditions. Of the genetic risk factors relevant to most cases of AD, the most well-known with the strongest contribution to risk is APOE, specifically the ε4 variant, whereas for cancer risk, APOE has not featured as a significant genetic contributor to risk. However, at the protein level in both conditions, ApoE contributes to disease pathology via affecting lipid physiology and transport. In AD, Aβ-dependent and -independent interactions have been suggested, whereas in cancer, ApoE plays a role in immunoregulation. Understanding the mechanism of action of ApoE in these diametrically opposed diseases may enable differential targeting of therapeutics to provide a beneficial outcome for both.
Collapse
Affiliation(s)
- Claire M. Perks
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Rachel M. Barker
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Mai Alhadrami
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Omar Alkahtani
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Emily Gill
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Mary Grishaw
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
| | - Abigail J. Harland
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Peter Henley
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
| | - Haonan Li
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Ellie O’Sullivan
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
| | - Gideon Stone
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
| | - Xiaoyu Su
- Cancer Endocrinology Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (R.M.B.); (M.A.); (O.A.); (E.G.); (A.J.H.); (H.L.); (X.S.)
| | - Patrick G. Kehoe
- Cerebrovascular and Dementia Research Group, Bristol Medical School, Learning & Research Building, Level 2, Southmead Hospital, Bristol BS10 5NB, UK; (M.G.); (P.H.); (E.O.); (G.S.)
| |
Collapse
|
39
|
Tanaka J, Nakagawa T, Ono Y, Kamura Y, Ishida T, Kawabata H, Takahashi K, Sato H, Liss AS, Mizukami Y, Yokoi T. Highly multiplexed digital PCR assay for simultaneous quantification of variant allele frequencies and copy number alterations of KRAS and GNAS in pancreatic cancer precursors. Mol Oncol 2025. [PMID: 40077847 DOI: 10.1002/1878-0261.70011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2024] [Revised: 12/18/2024] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasms (IPMNs) are pancreatic ductal adenocarcinoma (PDAC) precursor lesions. Detecting these precursors and monitoring their progression are crucial for early PDAC diagnosis. Digital PCR (dPCR) is a highly sensitive nucleic acid quantification technique and offers a cost-effective option for patient follow-up. However, the clinical utility of conventional dPCR is restricted by multiplexing constraints, particularly due to the challenge of simultaneously quantifying multiple mutations and amplifications. In this study, we applied highly multiplexed dPCR and melting curve analysis to simultaneously measure single nucleotide mutations and amplifications of KRAS and GNAS. The developed 14-plex assay included both wild-type and mutant KRAS, a common driver gene in both PanIN and IPMN, and GNAS, which is specifically mutated in IPMN, along with RPP30, a reference gene for copy number alterations (CNAs). This multiplex dPCR method detected all target mutations with a limit of detection below 0.2% while quantifying CNAs. Additionally, the assay accurately quantified variant allele frequencies in liquid biopsy and tissue samples from both pancreatic neoplasm precursor and PDAC patients, indicating its potential for use in comprehensive patient follow-up.
Collapse
Affiliation(s)
- Junko Tanaka
- Center for Digital Services - Healthcare, Research & Development Group, Hitachi, Ltd., Tokyo, Japan
| | - Tatsuo Nakagawa
- Center for Digital Services - Healthcare, Research & Development Group, Hitachi, Ltd., Tokyo, Japan
| | - Yusuke Ono
- Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Japan
- Department of Advanced Genomic Community Healthcare, Asahikawa Medical University, Japan
| | - Yoshio Kamura
- Center for Digital Services - Healthcare, Research & Development Group, Hitachi, Ltd., Tokyo, Japan
| | - Takeshi Ishida
- Center for Digital Services - Healthcare, Research & Development Group, Hitachi, Ltd., Tokyo, Japan
| | - Hidemasa Kawabata
- Division of Gastroenterology, Department of Medicine, Asahikawa Medical University, Japan
| | - Kenji Takahashi
- Department of Advanced Genomic Community Healthcare, Asahikawa Medical University, Japan
- Division of Gastroenterology, Department of Medicine, Asahikawa Medical University, Japan
| | - Hiroki Sato
- Division of Gastroenterology, Department of Medicine, Asahikawa Medical University, Japan
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Andrew S Liss
- Division of Gastrointestinal and Oncologic Surgery, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Yusuke Mizukami
- Institute of Biomedical Research, Sapporo Higashi Tokushukai Hospital, Japan
- Department of Advanced Genomic Community Healthcare, Asahikawa Medical University, Japan
- Division of Gastroenterology, Department of Medicine, Asahikawa Medical University, Japan
| | - Takahide Yokoi
- Center for Digital Services - Healthcare, Research & Development Group, Hitachi, Ltd., Tokyo, Japan
| |
Collapse
|
40
|
Jin K, Xu J, Zhang L, Liu Z, Su X, Xu Z, Ding Y, Liu H, Chang Y, Xu L, Wang Z, Zhu Y, Xu J. TERT promoter mutations or protein overexpression define an aggressive subset with favourable immunotherapeutic response in advanced urothelial carcinoma. BMJ ONCOLOGY 2025; 4:e000586. [PMID: 40099003 PMCID: PMC11911668 DOI: 10.1136/bmjonc-2024-000586] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/24/2024] [Accepted: 03/03/2025] [Indexed: 03/19/2025]
Abstract
Objective Telomerase reverse transcriptase (TERT) gene promoter mutation (TPM) is a key non-coding somatic alteration in urothelial carcinoma (UC) that plays a critical role in telomerase activation. Despite its importance, the prognostic value of TPM has shown mixed results in previous studies. Methods and analysis This study included 155 UC patients from two local clinical centres and 1652 patients from four public datasets, along with matched clinical annotation. Immunohistochemistry of TERT and immune-related markers was performed on tissue microarrays, and transcriptomic and genomic data were analysed to evaluate immune microenvironment characteristics and mutational profiles associated with TPM. We assessed the association of TPM or TERT overexpression (OE) with clinical outcomes, genomics and immunological profiles across tumour stages. Results In early-stage UC, TPM or TERT OE was not significantly associated with patient outcomes. However, in advanced urothelial carcinoma (aUC), TPM or TERT OE was linked to markedly worse overall survival (OS) and a poor response to platinum-based chemotherapy. Notably, despite this unfavourable prognosis, these patients exhibited a more favourable response to anti-PD-1/PD-L1 immunotherapy. aUC with TPM or TERT OE was characterised by an immune-evasive microenvironment, including infiltration of exhausted CD8+ T cells and elevated PD-1 and PD-L1 expression. Furthermore, genomic analysis further revealed a higher APOBEC mutational signature and a lower clock-like mutational signature in aUC with TPM or TERT OE. Conclusion In this retrospective study, TPM or TERT OE identifies a more aggressive subset of patients with poor OS and an immune-evasive microenvironment but a better response to immunotherapy in aUC.
Collapse
Affiliation(s)
- Kaifeng Jin
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jingtong Xu
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Lingkai Zhang
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Zhaopei Liu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Xiaohe Su
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Ziyue Xu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yawei Ding
- Department of Immunology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Hailong Liu
- Department of Urology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Yuan Chang
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Le Xu
- Department of Urology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zewei Wang
- Department of Urology, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yu Zhu
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Jiejie Xu
- NHC Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| |
Collapse
|
41
|
Mahipal A, Bucheit L, Zhang N, Barnett RM, Storandt MH, Chakrabarti S. Frequency and outcomes of BRAF alterations identified by liquid biopsy in metastatic, non-colorectal gastrointestinal cancers. Oncologist 2025; 30:oyaf044. [PMID: 40163685 PMCID: PMC11957259 DOI: 10.1093/oncolo/oyaf044] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2024] [Accepted: 02/04/2025] [Indexed: 04/02/2025] Open
Abstract
BACKGROUND Impact of BRAF V600E mutations (BRAFV600E), a poor prognostic factor in metastatic colorectal cancer, is lacking in non-CRC gastrointestinal (GI) cancers including pancreatic (PDAC), gastric/gastroesophageal (GEA), hepatocellular carcinoma (HCC), and cholangiocarcinoma (CCA). Due to tumor-agnostic approvals for patients with BRAFV600E, understanding the frequency and impact of BRAF alterations across non-CRC GI cancers is essential for clinical decision-making. METHODS Patients with PDAC, GEA, HCC, or CCA who had cell-free DNA detected on Guardant360 (Guardant Health) from 2020 to 2023 were queried. Prevalence of characterized BRAF genomic alterations (GA) was calculated; GAs were grouped by class (Class I/II/III). The Chi-squared test assessed differences between cancer types. A subset of patients had outcomes analysis using GuardantINFORM, a real-world clinicogenomic database, to derive real-world overall survival (rwOS). RESULTS Of 32 480 included patients, BRAF GAs were identified in 4.4%; 19% were BRAFV600E (0.81% prevalence overall). CCA had the highest rate of BRAF GAs and BRAFV600E (P < .01); HCC and GEA had the highest rates of BRAF class II/III alterations. There were no significant differences in rwOS by alteration class or cancer type; numeric differences were observed by alteration class. Few patients were treated with BRAF inhibitors (2.2%). Prevalence of co-occurring alterations was unique by cancer type. CONCLUSIONS Frequency of BRAF GAs, including BRAFV600E, in non-CRC GI cancers detected by liquid biopsy is similar to tissue-based rates and can be reliably used to assess BRAF status. BRAF GAs have mixed prognostic implications on survival for patients with non-CRC GI malignancies that warrant further exploration.
Collapse
Affiliation(s)
- Amit Mahipal
- University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, United States
- Mayo Clinic, Rochester, MN, United States
| | | | - Nicole Zhang
- Guardant Health Inc, Palo Alto, CA, United States
| | | | | | - Sakti Chakrabarti
- University Hospitals Seidman Cancer Center, Case Western Reserve University, Cleveland, OH, United States
| |
Collapse
|
42
|
Nguyen LTT, Thompson EK, Bhimani N, Duong MC, Nguyen HG, Bullock M, Gild ML, Glover A. Prognostic Significance of Key Molecular Markers in Thyroid Cancer: A Systematic Literature Review and Meta-Analysis. Cancers (Basel) 2025; 17:939. [PMID: 40149275 PMCID: PMC11940365 DOI: 10.3390/cancers17060939] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2025] [Revised: 02/28/2025] [Accepted: 03/06/2025] [Indexed: 03/29/2025] Open
Abstract
Background: Thyroid cancer (TC) involves diverse genetic alterations, with their prognostic significance often debated. Objectives: This study evaluates the impact of BRAF, TERT promoter, TP53, and PI3K pathway mutations detected via Next-Generation Sequencing (NGS) on overall survival (OS) and disease-free survival (DFS) in follicular-derived TC patients. Methods: A comprehensive search was conducted in MEDLINE, Scopus, and EMBASE databases from 2013 to 2023 for studies using NGS on TC patients. Hazard ratios (HR) and 95% confidence intervals (CI) for OS and DFS were extracted from original studies or estimated from Kaplan-Meier curves (KMC). A random-effects model, weighted by inverse variance, was used to calculate pooled HRs. Publication bias was assessed using Egger's regression test and visual funnel plot analysis. Results: Of the 3921 initial studies, nine studies involving 1075 patients were included in the meta-analysis. BRAF mutations showed no significant effect on OS (HR = 1.11, 95% CI: 0.66-1.88) or DFS (HR = 1.23, 95% CI: 0.66-2.29). In contrast, TERT promoter mutations were strongly associated with worse OS (HR = 1.90, 95% CI: 1.17-3.09) and DFS (HR = 2.76, 95% CI: 1.86-4.10). TP53 and PI3K pathway mutations were linked to shorter OS (HR = 2.87, 95% CI: 1.44-5.86 and HR = 2.17, 95% CI: 1.05-4.15, respectively), though their impact on DFS remains unclear due to limited data. Conclusions: These findings highlight TERT promoter mutations as strong prognostic markers for both OS and DFS, while TP53 and PI3K mutations indicate higher mortality risk.
Collapse
Affiliation(s)
- Linh T. T. Nguyen
- Kolling Institute, Northern Sydney Local Health District and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia; (L.T.T.N.); (M.B.); (M.L.G.)
- Department of Endocrinology, The 108 Military Central Hospital, Hanoi 100000, Vietnam
| | - Emma K. Thompson
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2010, Australia; (E.K.T.); (N.B.)
| | - Nazim Bhimani
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2010, Australia; (E.K.T.); (N.B.)
- Specialty of Surgery, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
| | - Minh C. Duong
- School of Population Health, University of New South Wales, Sydney, NSW 2033, Australia;
| | - Huy G. Nguyen
- School of Biomedical Engineering, University of Technology Sydney, Sydney, NSW 2007, Australia;
| | - Martyn Bullock
- Kolling Institute, Northern Sydney Local Health District and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia; (L.T.T.N.); (M.B.); (M.L.G.)
| | - Matti L. Gild
- Kolling Institute, Northern Sydney Local Health District and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia; (L.T.T.N.); (M.B.); (M.L.G.)
- Department of Endocrinology, Royal North Shore Hospital, Northern Sydney Local Health District, Sydney, NSW 2065, Australia
| | - Anthony Glover
- Kolling Institute, Northern Sydney Local Health District and Sydney Medical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW 2050, Australia; (L.T.T.N.); (M.B.); (M.L.G.)
- The Kinghorn Cancer Centre, Garvan Institute of Medical Research, St. Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Darlinghurst, NSW 2010, Australia; (E.K.T.); (N.B.)
- Specialty of Surgery, Sydney Medical School, Faculty of Medicine and Health, The University of Sydney, Camperdown, NSW 2050, Australia
| |
Collapse
|
43
|
Nagarajan A, Amberg-Johnson K, Paull E, Huang K, Ghanakota P, Chandrasinghe A, Chief Elk J, Sampson JM, Wang L, Abel R, Albanese SK. Predicting Resistance to Small Molecule Kinase Inhibitors. J Chem Inf Model 2025; 65:2543-2557. [PMID: 39979081 DOI: 10.1021/acs.jcim.4c02313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/22/2025]
Abstract
Drug resistance is a critical challenge in treating diseases like cancer and infectious disease. This study presents a novel computational workflow for predicting on-target resistance mutations to small molecule inhibitors (SMIs). The approach integrates genetic models with alchemical free energy perturbation (FEP+) calculations to identify likely resistance mutations. Specifically, a genetic model, RECODE, leverages cancer-specific mutation patterns to prioritize probable amino acid changes. Physics-based calculations assess the impact of these mutations on protein stability, endogenous substrate binding, and inhibitor binding. We apply this approach retrospectively to gefitinib and osimertinib, two clinical epidermal growth factor receptor (EGFR) inhibitors used to treat nonsmall cell lung cancer (NSCLC). Among hundreds of possible mutations, the pipeline accurately predicted 4 out of 11 and 7 out of 19 known binding site mutations for gefitinib and osimertinib, respectively, including the clinically relevant T790M and C797S resistance mutations. This study demonstrates the potential of integrating genetic models and physics-based calculations to predict SMI resistance mutations. This approach can be applied to other kinases and target classes, potentially enabling the design of next-generation inhibitors with improved durability of response in patients.
Collapse
Affiliation(s)
- Anu Nagarajan
- Schrödinger, New York, New York 10036, United States
| | | | - Evan Paull
- Schrödinger, New York, New York 10036, United States
| | - Kunling Huang
- Schrödinger, New York, New York 10036, United States
| | | | | | | | | | - Lingle Wang
- Schrödinger, New York, New York 10036, United States
| | - Robert Abel
- Schrödinger, New York, New York 10036, United States
| | | |
Collapse
|
44
|
Zheng X, Sun Z, Wang S, Liu Q, Zhu B, Ren Z, Fan D, Zhang C, Fu X, Jin Y, Luo J, Wang J, Ren B. SKA3 promotes lung adenocarcinoma progression via the EGFR/E2F1/SKA3/integrin β1 signaling loop. Mol Cell Biochem 2025:10.1007/s11010-025-05242-x. [PMID: 40056339 DOI: 10.1007/s11010-025-05242-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2024] [Accepted: 02/22/2025] [Indexed: 03/10/2025]
Abstract
Spindle and kinetochore-associated complex subunit 3 (SKA3) contributes to tumor growth and metastasis, but its specific roles have not been clearly elucidated. In this study, we found that SKA3 contributed to lung adenocarcinoma (LUAD) progression by interacting with integrin β1. The expression characteristics of SKA3 in LUAD patients were analyzed by The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets and validated in 33 paired LUAD tissues by immunohistochemistry. Our data confirmed that SKA3 was a crucial regulator of LUAD progression and was associated with worse patient survival. In vitro and in vivo studies showed that SKA3 increased cell migration and invasion. Mechanistically, it was demonstrated that SKA3 could bind to integrin β1 and promote its activation, which further promoted the activation of EGFR. As a positive feedback loop, the activation of EGFR in turn promoted the expression of SKA3 via E2F1-mediated transcriptional regulation. Inhibition of EGFR with AZD9291 blocked SKA3 signaling induced by E2F1. These results indicated that SKA3 was crucial for the activation of EGFR and its downstream signaling pathway. Our findings uncovered the oncogenic role of SKA3 in LUAD progression and elucidated a novel EGFR/E2F1/SKA3/integrin β1 signaling loop, providing a potential SKA3-directed therapeutic strategy for LUAD patients.
Collapse
Affiliation(s)
- Xiufen Zheng
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Nanjing, 210009, China
- Department of Pharmacy, The First Affiliated Hospital of Hainan Medical University, Hainan, 570102, China
| | - Zedong Sun
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Nanjing, 210009, China
| | - Shi Wang
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Nanjing, 210009, China
- Department of Surgery, Wu Han Wu Chang Hospital, Wuhan, 430063, China
| | - Qibing Liu
- Department of Pharmacy, The First Affiliated Hospital of Hainan Medical University, Hainan, 570102, China
| | - Biqing Zhu
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Nanjing, 210009, China
| | - Zhijian Ren
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Nanjing, 210009, China
| | - Dingwei Fan
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Nanjing, 210009, China
| | - Chunping Zhang
- Department of Pharmacy, The First Affiliated Hospital of Hainan Medical University, Hainan, 570102, China
| | - Xinyin Fu
- Department of Pharmacy, The First Affiliated Hospital of Hainan Medical University, Hainan, 570102, China
| | - Yan Jin
- Department of Pharmacy, The First Affiliated Hospital of Hainan Medical University, Hainan, 570102, China
| | - Jing Luo
- Department of Cardiothoracic Surgery, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210000, China.
| | - Jie Wang
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Nanjing, 210009, China.
| | - Binhui Ren
- Department of Thoracic Surgery, Jiangsu Key Laboratory of Molecular and Translational Cancer Research, Jiangsu Cancer Hospital and Nanjing Medical University Affiliated Cancer Hospital and Jiangsu Institute of Cancer Research, 42 Baiziting Road, Nanjing, 210009, China.
| |
Collapse
|
45
|
Jafari P, Forrest M, Segal J, Wang P, Tjota MY. Pan-Cancer Molecular Biomarkers: Practical Considerations for the Surgical Pathologist. Mod Pathol 2025; 38:100752. [PMID: 40058460 DOI: 10.1016/j.modpat.2025.100752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 02/25/2025] [Accepted: 02/26/2025] [Indexed: 03/29/2025]
Abstract
Traditional anatomic pathologic classification of cancer is based on tissue of origin and morphologic and immunohistochemical characterization of the malignant cells. With the technological improvements of massively parallel or next-generation sequencing, oncogenic drivers that are shared across different tumor types are increasingly being identified and used as pan-cancer biomarkers. This approach is reflected in the growing list of Food and Drug Administration-approved tumor-agnostic therapies, including pembrolizumab in the setting of microsatellite instability and high tumor mutational burden, larotrectinib and entrectinib for solid tumors with NTRK fusions, and combined dabrafenib-trametinib for BRAF V600E-mutated neoplasms. Several other biomarkers are currently under investigation, including fibroblast growth factor receptor (FGFR), RET, and ROS1 fusions; ERBB2 amplification; and mutations in the AKT1/2/3, NF1, RAS pathway and (mitogen-activated protein kinase (MAPK) pathway. As molecular assays are increasingly incorporated into routine tumor workup, the emergence of additional pan-cancer biomarkers is likely to be a matter more of "when" than "if." In this review, we first explore some of the conceptual and technical considerations at the intersection of surgical and molecular pathology, followed by a brief overview of both established and emerging molecular pan-cancer biomarkers and their diagnostic and clinical applications.
Collapse
Affiliation(s)
- Pari Jafari
- Department of Pathology, The University of Chicago, Chicago, Illinois
| | - Megan Forrest
- Department of Pathology, The University of Chicago, Chicago, Illinois
| | - Jeremy Segal
- Department of Pathology, The University of Chicago, Chicago, Illinois
| | - Peng Wang
- Department of Pathology, The University of Chicago, Chicago, Illinois
| | | |
Collapse
|
46
|
Zhang K, Qiu Y, Feng S, Yin H, Liu Q, Zhu Y, Cui H, Wei X, Wang G, Wang X, Shen Y. Development of model for identifying homologous recombination deficiency (HRD) status of ovarian cancer with deep learning on whole slide images. J Transl Med 2025; 23:267. [PMID: 40038690 PMCID: PMC11877705 DOI: 10.1186/s12967-025-06234-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2024] [Accepted: 02/11/2025] [Indexed: 03/06/2025] Open
Abstract
BACKGROUND Homologous recombination deficiency (HRD) refers to the dysfunction of homologous recombination repair (HRR) at the cellular level. The assessment of HRD status has the important significance for the formulation of treatment plans, efficacy evaluation, and prognosis prediction of patients with ovarian cancer. OBJECTIVES This study aimed to construct a deep learning-based classifier for identifying tumor regions from whole slide images (WSIs) and stratify the HRD status of patients with ovarian cancer (OC). METHODS The deep learning models were trained on 205 H&E-stained sections which contained 205 ovarian cancer patients, 64 were found to have HRD status while 141 had homologous recombination proficiency (HRP) status from two institutions Memorial Sloan Kettering Cancer Center (MSKCC) and Zhongda Hospital, Southeast University. The framework includes tumor regions identification by UNet + + and subtypes of ovarian cancer classifier construction. Referring to the EasyEnsemble, we classified the HRP patients into three distributed subsets. These three subsets of HRP patients were combined with the HRD patients to establish three new training groups for subsequent model construction. The three models were integrated into a single model named Ensemble Model. RESULTS The UNet + + algorithm segmented tumor regions with 81.8% accuracy, 85.9% recall, 83.8% dice score and 68.3% IoU. The AUC of the Ensemble Model was 0.769 (Precision = 0.800, Recall = 0.727, F1-score = 0.762) in the study. The most discriminative features between HRD and HRP comprised S_mean_dln_obtuse_ratio, S_mean_dln_acute_ratio and mean_Graph_T-S_Betweenness_normed. CONCLUSIONS The models we constructed enables accurate discrimination between tumor and non-tumor tissues in ovarian cancer as well as the prediction of HRD status for patients with ovarian cancer.
Collapse
Affiliation(s)
- Ke Zhang
- Department of Obstetrics and Gynaecology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Youhui Qiu
- Institute for AI in Medicine, School of Artificial Intelligence, Nanjing University of Information Science and Technology, Nanjing, China
| | - Songwei Feng
- Department of Obstetrics and Gynaecology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Han Yin
- Department of Obstetrics and Gynaecology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Qi Liu
- Department of Obstetrics and Gynaecology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Yuxin Zhu
- Department of Obstetrics and Gynaecology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China
| | - Haoyu Cui
- Institute for AI in Medicine, School of Artificial Intelligence, Nanjing University of Information Science and Technology, Nanjing, China
| | - Xiaoying Wei
- Department of Pathology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Guoqing Wang
- Department of Pathology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, China
| | - Xiangxue Wang
- Institute for AI in Medicine, School of Artificial Intelligence, Nanjing University of Information Science and Technology, Nanjing, China.
| | - Yang Shen
- Department of Obstetrics and Gynaecology, School of Medicine, Zhongda Hospital, Southeast University, Nanjing, 210009, China.
| |
Collapse
|
47
|
Maciag AE, Stice JP, Wang B, Sharma AK, Chan AH, Lin K, Singh D, Dyba M, Yang Y, Setoodeh S, Smith BP, Ju JH, Jeknic S, Rabara D, Zhang Z, Larsen EK, Esposito D, Denson JP, Ranieri M, Meynardie M, Mehdizadeh S, Alexander PA, Abreu Blanco M, Turner DM, Xu R, Lightstone FC, Wong KK, Stephen AG, Wang K, Simanshu DK, Sinkevicius KW, Nissley DV, Wallace E, McCormick F, Beltran PJ. Discovery of BBO-8520, a First-In-Class Direct and Covalent Dual Inhibitor of GTP-Bound (ON) and GDP-Bound (OFF) KRASG12C. Cancer Discov 2025; 15:578-594. [PMID: 39642212 PMCID: PMC11873722 DOI: 10.1158/2159-8290.cd-24-0840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 10/02/2024] [Accepted: 11/26/2024] [Indexed: 12/08/2024]
Abstract
Approved inhibitors of KRASG12C prevent oncogenic activation by sequestering the inactive, GDP-bound (OFF) form rather than directly binding and inhibiting the active, GTP-bound (ON) form. This approach provides no direct target coverage of the active protein. Expectedly, adaptive resistance to KRASG12C (OFF)-only inhibitors is observed in association with increased expression and activity of KRASG12C(ON). To provide optimal KRASG12C target coverage, we have developed BBO-8520, a first-in-class, direct dual inhibitor of KRASG12C(ON) and (OFF) forms. BBO-8520 binds in the Switch-II/Helix3 pocket, covalently modifies the target cysteine, and disables effector binding to KRASG12C(ON). BBO-8520 exhibits potent signaling inhibition in growth factor-activated states, in which current (OFF)-only inhibitors demonstrate little measurable activity. In vivo, BBO-8520 demonstrates rapid target engagement and inhibition of signaling, resulting in durable tumor regression in multiple models, including those resistant to KRASG12C(OFF)-only inhibitors. BBO-8520 is in phase 1 clinical trials in patients with KRASG12C non-small cell lung cancer. Significance: BBO-8520 is a first-in-class direct, small molecule covalent dual inhibitor that engages KRASG12C in the active (ON) and inactive (OFF) conformations. BBO-8520 represents a novel mechanism of action that allows for optimal target coverage and delays the emergence of adaptive resistance seen with (OFF)-only inhibitors in the clinic. See related commentary by Zhou and Westover, p. 455.
Collapse
Affiliation(s)
- Anna E. Maciag
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - James P. Stice
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Bin Wang
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Alok K. Sharma
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Albert H. Chan
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Ken Lin
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Devansh Singh
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Marcin Dyba
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Yue Yang
- Physical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California
| | - Saman Setoodeh
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Brian P. Smith
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Jin Hyun Ju
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Stevan Jeknic
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Dana Rabara
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Zuhui Zhang
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Erik K. Larsen
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Dominic Esposito
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - John-Paul Denson
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Michela Ranieri
- Perlmutter Cancer Center, New York University, New York, New York
| | - Mary Meynardie
- Perlmutter Cancer Center, New York University, New York, New York
| | - Sadaf Mehdizadeh
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Patrick A. Alexander
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Maria Abreu Blanco
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - David M. Turner
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Rui Xu
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Felice C. Lightstone
- Physical and Life Sciences (PLS) Directorate, Lawrence Livermore National Laboratory, Livermore, California
| | - Kwok-Kin Wong
- Perlmutter Cancer Center, New York University, New York, New York
| | - Andrew G. Stephen
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Keshi Wang
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Dhirendra K. Simanshu
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | | | - Dwight V. Nissley
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
| | - Eli Wallace
- BridgeBio Oncology Therapeutics, South San Francisco, California
| | - Frank McCormick
- NCI RAS Initiative, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc., Frederick, Maryland
- Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, California
| | - Pedro J. Beltran
- BridgeBio Oncology Therapeutics, South San Francisco, California
| |
Collapse
|
48
|
Patel V, Bhalla S. Commentary on A Pulmonary Nodule with an Unexpected Mutation Profile. Clin Chem 2025; 71:356-357. [PMID: 40037407 DOI: 10.1093/clinchem/hvae204] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2024] [Accepted: 10/29/2024] [Indexed: 03/06/2025]
Affiliation(s)
- Viral Patel
- Division of Hematology-Oncology, UT Southwestern Medical Center, Dallas, TX, United States
| | - Sheena Bhalla
- Division of Hematology-Oncology, UT Southwestern Medical Center, Dallas, TX, United States
- Harold C. Simmons Comprehensive Cancer Center, UT Southwestern Medical Center, Dallas, TX, United States
| |
Collapse
|
49
|
Omer DM, Shah F, Luthra A, Chen CT, Lee CI, Williams H, Walch H, Verheij FS, Rosen R, Alvarez J, Firat C, Karagkounis G, Weiser MR, Widmar M, Wei IH, Pappou EP, Nash GM, Smith JJ, Chatila WK, Romesser PB, Shia J, Paty PB, Garcia-Aguilar J, Sanchez-Vega F. Clinical and Genomic Characterization of Secondary Rectal Cancer After Radiotherapy for Prostate Cancer. JAMA Netw Open 2025; 8:e251039. [PMID: 40100215 PMCID: PMC11920846 DOI: 10.1001/jamanetworkopen.2025.1039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/30/2024] [Accepted: 01/15/2025] [Indexed: 03/20/2025] Open
Abstract
Importance Patients treated with radiotherapy (RT) for prostate cancer (PC) have increased risk of secondary rectal cancer (SRC) and more limited treatment options. Objective To assess the tumor molecular profile, clinical characteristics, and oncologic outcomes of SRC after PC and compare them with those of primary rectal cancer (PRC). Design, Setting, and Participants This case-control study included patients with SRC diagnosed 5 or more years after RT for PC and patients with PRC who were treated at Memorial Sloan Kettering Cancer Center in New York between February 1, 1994, and September 31, 2022. Main Outcomes and Measures Clinical information and DNA sequencing data were analyzed. Oncologic outcomes were compared between patients with SRC and clinically matched patients with PRC using log-rank tests and Cox proportional hazards regression models. Numerical and categorical variables were compared using the Wilcoxon rank sum test and Fisher exact test, respectively. Results The analysis included 604 male patients with PRC (71.6%; median age, 55 [IQR, 46-66] years) and 64 male patients with SRC (median age, 78 [IQR, 72-82] years). Patients with SRC had more distal rectum (37 of 63 [58.7%] vs 131 of 581 [22.5%]; P < .001) and anterior rectal wall (20 of 57 [35.1%] vs 67 of 496 [13.5%]; P < .001) tumors, were less likely to receive neoadjuvant treatment (33 of 64 [51.6%] vs 570 of 604 [94.4%]), and had shorter 5-year overall survival (45.7% vs 64.9%; P = .01) and disease-free survival (40.3% vs 71.2%; P = .006) compared with clinically matched patients with PRC. Targeted DNA sequencing data from 31 SRC tumors identified lower mutational burden (median, 4.4 [IQR, 3.2-6.7] per megabase [Mb] vs 5.8 [IQR, 4.4-7.0] per Mb; P = .047), lower frequency of APC alterations (15 [48.4%] vs 432 [79.9%]; P < .001), and higher rates of SMAD4 inactivation (8 [25.8%] vs 54 [10.0%]; P = .01) compared with 541 PRC tumors. Whole-exome sequencing data from 17 SRC tumors identified a higher rate of frameshift deletions compared with 28 PRC tumors (median, 5.0 [IQR, 4.0-9.0] vs 2.5 [IQR, 1.0-4.2] variants; P < .001). Conclusions and Relevance In this case-control study, patients with SRC after RT for PC had worse survival and different molecular profiles than patients with PRC. These findings may help improve the clinical management of SRC.
Collapse
Affiliation(s)
- Dana M. Omer
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Farheen Shah
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Anisha Luthra
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Chin-Tung Chen
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Christina I. Lee
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Hannah Williams
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Henry Walch
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Floris S. Verheij
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Roni Rosen
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Janet Alvarez
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Canan Firat
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Georgios Karagkounis
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Martin R. Weiser
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Maria Widmar
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Iris H. Wei
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Emmanouil P. Pappou
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Garrett M. Nash
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - J. Joshua Smith
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Walid K. Chatila
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Paul B. Romesser
- Department of Radiation Oncology, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Jinru Shia
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Philip B. Paty
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Julio Garcia-Aguilar
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
| | - Francisco Sanchez-Vega
- Department of Surgery, Colorectal Service, Memorial Sloan Kettering Cancer Center, New York, New York
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York
| |
Collapse
|
50
|
Oike T, Kambe R, Darwis NDM, Shibata A, Ohno T. Establishment of cancer cell radiosensitivity database linked to multi-layer omics data. Cancer Sci 2025; 116:690-697. [PMID: 39668120 PMCID: PMC11875790 DOI: 10.1111/cas.16334] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2024] [Revised: 08/20/2024] [Accepted: 08/23/2024] [Indexed: 12/14/2024] Open
Abstract
Personalized radiotherapy based on the intrinsic sensitivity of individual tumors is anticipated, however, it has yet to be realized. To explore cancer radiosensitivity, analysis in combination with omics data is important. The Cancer Cell Line Encyclopedia (CCLE) provides multi-layer omics data for hundreds of cancer cell lines. However, the radiosensitivity counterpart is lacking. To address this issue, we aimed to establish a database of radiosensitivity, as assessed by the gold standard clonogenic assays, for the CCLE cell lines by collecting data from the literature. A deep learning-based screen of 33,284 papers identified 926 relevant studies, from which SF2 (survival fraction after 2 Gy irradiation) data were extracted. The median SF2 (mSF2) was calculated for each cell line, generating an mSF2 database comprising 285 cell lines from 28 cancer types. The mSF2 showed a normal distribution among higher and lower cancer-type hierarchies, demonstrating a large variation across and within cancer types. In selected cell lines, mSF2 correlated significantly with the single-institution SF2 obtained using standardized experimental protocols or with integral survival, a radiosensitivity index that correlates with clonogenic survival. Notably, the mSF2 for blood cancer cell lines was significantly lower than that for solid cancer cell lines, which is in line with the empirical knowledge that blood cancers are radiosensitive. Furthermore, the CCLE-derived protein levels of NFE2L2 and SQSTM1, which are involved in antioxidant damage responses that confer radioresistance, correlated significantly with mSF2. These results suggest the robustness and potential utility of the mSF2 database, linked to multi-layer omics data, for exploring cancer radiosensitivity.
Collapse
Affiliation(s)
- Takahiro Oike
- Gunma University Heavy Ion Medical CenterMaebashiGunmaJapan
- Department of Radiation OncologyGunma University Graduate School of MedicineMaebashiGunmaJapan
| | - Ryosuke Kambe
- Department of Radiation OncologyGunma University Graduate School of MedicineMaebashiGunmaJapan
| | - Narisa Dewi Maulany Darwis
- Department of Radiation OncologyGunma University Graduate School of MedicineMaebashiGunmaJapan
- Department of Radiation OncologyDr. Cipto Mangunkusumo National General Hospital – Faculty of Medicine Universitas IndonesiaJakartaIndonesia
| | - Atsushi Shibata
- Division of Molecular Oncological Pharmacy, Graduate School of Pharmaceutical SciencesKeio UniversityTokyoJapan
| | - Tatsuya Ohno
- Gunma University Heavy Ion Medical CenterMaebashiGunmaJapan
- Department of Radiation OncologyGunma University Graduate School of MedicineMaebashiGunmaJapan
| |
Collapse
|