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Lakbir S, de Wit R, de Bruijn I, Kundra R, Madupuri R, Gao J, Schultz N, Meijer GA, Heringa J, Fijneman RJA, Abeln S. Tumor break load quantitates structural variant-associated genomic instability with biological and clinical relevance across cancers. NPJ Precis Oncol 2025; 9:140. [PMID: 40369102 PMCID: PMC12078582 DOI: 10.1038/s41698-025-00922-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2024] [Accepted: 04/24/2025] [Indexed: 05/16/2025] Open
Abstract
While structural variants (SVs) are a clear sign of genomic instability, they have not been systematically quantified per patient since declining costs have only recently enabled large-scale profiling. Therefore, the biological and clinical impact of high numbers of SVs in patients is unknown. We introduce tumor break load (TBL), defined as the sum of unbalanced SVs, as a measure for SV-associated genomic instability. Using pan-cancer data from TCGA, PCAWG, and CCLE, we show that a high TBL is associated with significant changes in gene expression in 26/31 cancer types that consistently involve upregulation of DNA damage repair and downregulation of immune response pathways. Patients with a high TBL show a higher risk of recurrence and shorter median survival times for 5/15 cancer types. Our data demonstrate that TBL is a biologically and clinically relevant feature of genomic instability that may aid patient prognostication and treatment stratification. For the datasets analyzed in this study, TBL has been made available in cBioPortal.
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Affiliation(s)
- Soufyan Lakbir
- Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- AI Technology for Life Group, Department of Information and Computing Science; Department of Biology, Utrecht University, Utrecht, The Netherlands
| | - Renske de Wit
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
- AI Technology for Life Group, Department of Information and Computing Science; Department of Biology, Utrecht University, Utrecht, The Netherlands
| | - Ino de Bruijn
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | - Ritika Kundra
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | | | - Jianjiong Gao
- Memorial Sloan Kettering Cancer Center, New York City, NY, USA
| | | | - Gerrit A Meijer
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands
| | - Jaap Heringa
- Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands
| | - Remond J A Fijneman
- Translational Gastrointestinal Oncology Group, Department of Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.
| | - Sanne Abeln
- Bioinformatics Section, Department of Computer Science, Vrije Universiteit Amsterdam, Amsterdam, The Netherlands.
- AI Technology for Life Group, Department of Information and Computing Science; Department of Biology, Utrecht University, Utrecht, The Netherlands.
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2
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Li F, Zhang Y, Li C, Sun Q, Liu J, Qin T, Xu Z, Li B, Qu S, Pan L, Gao Q, Jiao M, Xiao Z. GATA1 insufficiencies in dysmegakaryopoiesis of myelodysplastic syndromes/neoplasms. Pathol Res Pract 2025; 269:155930. [PMID: 40168773 DOI: 10.1016/j.prp.2025.155930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Revised: 02/25/2025] [Accepted: 03/26/2025] [Indexed: 04/03/2025]
Abstract
GATA1 is one of critical transcription factors for megakaryopoiesis and platelet production. Our study aimed to explore the correlations between GATA1 expression and dysmegakaryopoiesis in myelodysplastic syndromes/neoplasm (MDS). We assessed GATA1 expression level of megakaryocytes by performing immunohistochemical staining on bone marrow biopsy sections from MDS patients. According to GATA1 expression level of megakaryocytes and positive megakaryocyte percentage, we assigned each patient a GATA1 score. Compared with TP53-wildtype patients, GATA1 scores significantly decreased in TP53-mutated patients (P < 0.001). Patients with abnormal karyotypes showed decreased GATA1 scores than those with normal karyotypes (P = 0.024). GATA1 expression levels were significantly downregulated in dysplastic megakaryocytes, especially micromegakaryocytes (P < 0.001). Furthermore, we explored the correlation between GATA1 expression levels and cytogenetic abnormalities of the same megakaryocyte using the morphology antibody chromosome (MAC) technique on fresh bone marrow smears. We found that GATA1-negative megakaryocytes had higher frequencies of cytogenetic abnormalities. Our results indicated that decreased GATA1 expression level of megakaryocytes was significantly associated with TP53 mutations, abnormal karyotypes and dysmegakaryopoiesis in MDS, suggesting that downregulation of GATA1 expression levels of megakaryocytes plays a critical role in the pathogenesis of MDS.
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Affiliation(s)
- Fuhui Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Yudi Zhang
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Chengwen Li
- Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Qi Sun
- Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Jinqin Liu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Tiejun Qin
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Zefeng Xu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Bing Li
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Shiqiang Qu
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Lijuan Pan
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Qingyan Gao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Meng Jiao
- MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China
| | - Zhijian Xiao
- State Key Laboratory of Experimental Hematology, National Clinical Research Center for Blood Diseases, Haihe Laboratory of Cell Ecosystem, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; MDS and MPN Centre, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China; Hematologic Pathology Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Tianjin, China.
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3
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Lopez-Nieto M, Sun Z, Relton E, Safakli R, Freibaum BD, Taylor JP, Ruggieri A, Smyrnias I, Locker N. Activation of the mitochondrial unfolded protein response regulates the dynamic formation of stress granules. J Cell Sci 2025; 138:jcs263548. [PMID: 39463355 DOI: 10.1242/jcs.263548] [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: 09/17/2024] [Accepted: 10/08/2024] [Indexed: 10/29/2024] Open
Abstract
To rapidly adapt to harmful changes to their environment, cells activate the integrated stress response (ISR). This results in an adaptive transcriptional and translational rewiring, and the formation of biomolecular condensates named stress granules (SGs), to resolve stress. In addition to this first line of defence, the mitochondrial unfolded protein response (UPRmt) activates a specific transcriptional programme to maintain mitochondrial homeostasis. We present evidence that the SG formation and UPRmt pathways are intertwined and communicate. UPRmt induction results in eIF2α phosphorylation and the initial and transient formation of SGs, which subsequently disassemble. The induction of GADD34 (also known as PPP1R15A) during late UPRmt protects cells from prolonged stress by impairing further assembly of SGs. Furthermore, mitochondrial functions and cellular survival are enhanced during UPRmt activation when SGs are absent, suggesting that UPRmt-induced SGs have an adverse effect on mitochondrial homeostasis. These findings point to a novel crosstalk between SGs and the UPRmt that might contribute to restoring mitochondrial functions under stressful conditions.
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Affiliation(s)
- Marta Lopez-Nieto
- Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7HX, UK
- The Pirbright Institute, Pirbright GU24 0NF, UK
| | - Zhaozhi Sun
- Heidelberg University, Medical Faculty, Centre for Integrative Infectious Disease Research (CIID), Department of Infectious Diseases, Molecular Virology, Heidelberg 69120, Germany
| | - Emily Relton
- Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7HX, UK
- The Pirbright Institute, Pirbright GU24 0NF, UK
| | - Rahme Safakli
- Faculty of Health and Medical Sciences, School of Veterinary Medicine, University of Surrey, Guildford GU2 7HX, UK
| | - Brian D Freibaum
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - J Paul Taylor
- Department of Cell and Molecular Biology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA
| | - Alessia Ruggieri
- Heidelberg University, Medical Faculty, Centre for Integrative Infectious Disease Research (CIID), Department of Infectious Diseases, Molecular Virology, Heidelberg 69120, Germany
| | - Ioannis Smyrnias
- Faculty of Health and Medical Sciences, School of Veterinary Medicine, University of Surrey, Guildford GU2 7HX, UK
| | - Nicolas Locker
- Faculty of Health and Medical Sciences, School of Biosciences and Medicine, University of Surrey, Guildford GU2 7HX, UK
- The Pirbright Institute, Pirbright GU24 0NF, UK
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Bai S, Wang Y, Zhou Y, Qiao L. Multi-omics pan-cancer analysis of monocyte to macrophage differentiation-associated (MMD) and its significance in hepatocellular carcinoma. Cancer Biomark 2025; 42:18758592251329280. [PMID: 40393675 DOI: 10.1177/18758592251329280] [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: 05/22/2025]
Abstract
BackgroundMalignant tumors are serious diseases that endanger human health. Therefore, it is crucial to identify markers that facilitate tumor diagnosis and prognostic assessment.ObjectiveThis study analyzed the significance of Monocyte to macrophage differentiation-associated (MMD) in various tumors from multiple perspectives, to explore the possibility of using MMD as a novel tumor marker.MethodsUsing the R software, an examination of MMD levels was conducted across diverse human cancers and their influence on cancer outcomes. MMD methylation, mutations, and immune infiltration analyses of various tumors were performed. A Cox regression model was used to predict the survival rates of patients with hepatocellular carcinoma (HCC). Finally, MMD expression and function were validated in Hep-3B cells.ResultsMMD was aberrantly expressed in diverse tumors and can predict patient outcomes. Methylation and functional enrichment studies indicated possible function of MMD in tumor progression, whereas immune infiltration data suggested its involvement in tumor immune evasion. Cox regression analysis revealed that elevated MMD levels were independent predictors of HCC patient outcomes. The quantitative real-time polymerase chain reaction (qPCR) data demonstrated high MMD levels in Hep-3B cells, and its suppression impeded Hep-3B cell growth.ConclusionsMMD was abnormally expressed in various tumors and was closely associated with tumor prognosis. Thus, it had the potential to be used as a novel tumor marker.
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Affiliation(s)
- Suyang Bai
- The First School of Clinical Medicine, Lanzhou University, Lanzhou, China
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yuping Wang
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Yongning Zhou
- Gansu Province Clinical Research Center for Digestive Diseases, The First Hospital of Lanzhou University, Lanzhou, China
- Department of Gastroenterology, The First Hospital of Lanzhou University, Lanzhou, China
| | - Liang Qiao
- Storr Liver Centre, the Westmead Institute for Medical Research, The University of Sydney, Westmead, Australia
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5
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Hameed SA, Kolch W, Brennan DJ, Zhernovkov V. Direct cell interactions potentially regulate transcriptional programmes that control the responses of high grade serous ovarian cancer patients to therapy. Sci Rep 2025; 15:14484. [PMID: 40280979 PMCID: PMC12032223 DOI: 10.1038/s41598-025-98463-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2024] [Accepted: 04/11/2025] [Indexed: 04/29/2025] Open
Abstract
The tumour microenvironment is composed of a complex cellular network involving cancer, stromal and immune cells in dynamic interactions. A large proportion of this network relies on direct physical interactions between cells, which may impact patient responses to clinical therapy. Doublets in scRNA-seq are usually excluded from analysis. However, they may represent directly interacting cells. To decipher the physical interaction landscape in relation to clinical prognosis, we inferred a physical cell-cell interaction (PCI) network from 'biological' doublets in a scRNA-seq dataset of approximately 18,000 cells, obtained from 7 treatment-naive ovarian cancer patients. Focusing on cancer-stromal PCIs, we uncovered molecular interaction networks and transcriptional landscapes that stratified patients in respect to their clinical responses to standard therapy. Good responders featured PCIs involving immune cells interacting with other cell types including cancer cells. Poor responders lacked immune cell interactions, but showed a high enrichment of cancer-stromal PCIs. To explore the molecular differences between cancer-stromal PCIs between responders and non-responders, we identified correlating gene signatures. We constructed ligand-receptor interaction networks and identified associated downstream pathways. The reconstruction of gene regulatory networks and trajectory analysis revealed distinct transcription factor (TF) clusters and gene modules that separated doublet cells by clinical outcomes. Our results indicate (i) that transcriptional changes resulting from PCIs predict the response of ovarian cancer patients to standard therapy, (ii) that immune reactivity of the host against the tumour enhances the efficacy of therapy, and (iii) that cancer-stromal cell interaction can have a dual effect either supporting or inhibiting therapy responses.
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Affiliation(s)
- Sodiq A Hameed
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin, D04 V1W8, Ireland.
| | - Walter Kolch
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin, D04 V1W8, Ireland
- Conway Institute of Biomolecular & Biomedical Research, University College Dublin, Belfield, Dublin, D04 V1W8, Ireland
| | - Donal J Brennan
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin, D04 V1W8, Ireland
- UCD Gynaecological Oncology Group Catherine McAuley Research Centre, Mater Misericordiae University Hospital, Eccles Street, Dublin, D07 R2WY, Ireland
| | - Vadim Zhernovkov
- Systems Biology Ireland, School of Medicine, University College Dublin, Belfield, Dublin, D04 V1W8, Ireland
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Huang X, Pan Z, Shen L, Chen H, Chen C, Lv T, Mei Y. The mechanism of Weiqi decoction treating gastric cancer: a work based on network pharmacology and experimental verification. Hereditas 2025; 162:67. [PMID: 40259338 PMCID: PMC12012975 DOI: 10.1186/s41065-025-00434-3] [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: 12/23/2024] [Accepted: 04/08/2025] [Indexed: 04/23/2025] Open
Abstract
BACKGROUND Weiqi Decoction (WQD) is an empirical prescription traditionally used in China for the treatment of precancerous gastric cancer (GC) lesions. This study aimed to elucidate the potential pharmacological mechanisms of WQD in GC therapy. METHODS Active ingredients, corresponding targets, and GC-related genes were identified using public databases. A protein-protein interaction (PPI) network was constructed via the STRING database, and functional enrichment analyses were conducted using the DAVID platform. Gene expression and survival analyses were performed using the GEPIA database. Molecular docking was conducted with AutoDock Vina and visualized using PyMOL. The effects of WQD on GC cell viability, proliferation, migration, and invasion were evaluated through CCK-8, colony formation, and Transwell assays. RESULTS WQD contained 43 active ingredients targeting 751 potential genes, including 458 GC-related targets. Quercetin, luteolin, and kaempferol were identified as key active compounds. PPI network analysis revealed nine core targets, including TP53 and SRC, which may mediate the anti-GC effects of WQD. GO enrichment analysis indicated involvement in 726 biological processes, 91 cellular components, and 177 molecular functions, while KEGG pathway analysis suggested modulation of the AGE-RAGE, PI3K-Akt, and HIF-1 signaling pathways. GEPIA database analysis confirmed that EP300, HSP90AA1, HSP90AB1, SRC, and TP53 were highly expressed in GC. Molecular docking demonstrated strong binding affinities between the key active compounds and core targets. In vitro experiments further validated that WQD extract inhibited GC cell viability, proliferation, migration, and invasion. CONCLUSION WQD exhibits therapeutic potential against GC by regulating multiple targets and signaling pathways. These findings provide mechanistic insights into the pharmacological actions of WQD in GC treatment.
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Affiliation(s)
- Xu Huang
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, P.R. China
| | - Zhihong Pan
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
| | - Lei Shen
- Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan, Hubei, 430060, P.R. China.
| | - Huan Chen
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
| | - Chang Chen
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
| | - Tingting Lv
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
| | - Yuzhou Mei
- Department of Gastroenterology, The First College of Clinical Medical Science, China Three Gorges University, Jiefang Road No. 2, Xiling District, Yichang, Hubei, 443000, P.R. China
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Torasawa M, Yoshida T, Shiraishi K, Yagishita S, Ono H, Uehara Y, Miyakoshi J, Tateishi A, Igawa YS, Higashiyama RI, Mochizuki A, Masuda K, Matsumoto Y, Shinno Y, Okuma Y, Goto Y, Horinouchi H, Hamamoto R, Yamamoto N, Watanabe SI, Yatabe Y, Takahashi K, Kohno T, Ohe Y. Implications of EGFR expression on EGFR signaling dependency and adaptive immunity against EGFR-mutated lung adenocarcinoma. Lung Cancer 2025; 202:108494. [PMID: 40088580 DOI: 10.1016/j.lungcan.2025.108494] [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: 11/03/2024] [Revised: 02/09/2025] [Accepted: 03/10/2025] [Indexed: 03/17/2025]
Abstract
BACKGROUND In EGFR-mutated lung adenocarcinoma (EGFRm LUAD), EGFR mutations do not necessarily result in increased EGFR expression (EGFR-exp), which differs among patients. However, the factors influencing EGFR-exp and the impact of EGFR-exp on tumor characteristics in patients with EGFRm LUAD remain unclear. PATIENTS AND METHODS Whole-exome and RNA sequencing were performed for patients with early- and advanced-stage EGFRm LUAD. The patients were classified into low or high EGFR-exp groups based on the median transcripts per million. We retrospectively examined the association between EGFR-exp, genomic characteristics, downstream EGFR signaling activity, tumor microenvironment (TME) status, and clinical outcomes. RESULTS This study included 450 and 45 patients in the early- and advanced-stage cohorts, respectively. In both cohorts, the EGFR-exp low group exhibited a lower incidence of TP53 co-mutations and EGFR amplification and a higher incidence of EGFR subclonal mutations than the EGFR-exp high group. Furthermore, downstream EGFR signaling pathways, such as the MAPK signaling, were less activated in the EGFR-exp low group. However, this group showed significantly enriched adaptive immune response pathways (Q < 0.0001) and an immune-inflamed TME. Additionally, a low EGFR-exp was a significantly favorable factor for postoperative relapse (odds ratio [OR], 0.6; P = 0.04). However, in the advanced-stage cohort, a low EGFR-exp was a significant risk factor for non-responders to osimertinib (OR, 17.5; P = 0.03). CONCLUSIONS In EGFRm LUAD, significant associations were observed between EGFR-exp levels and both EGFR signaling pathways and adaptive immune status, which in turn influence clinical outcomes. This large-scale multi-omics analysis highlights the heterogeneity among patients with EGFRm LUAD and emphasizes the need to assess EGFR-exp levels alongside mutation status for optimal treatment strategies in EGFRm LUAD.
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Affiliation(s)
- Masahiro Torasawa
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan; Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Tatsuya Yoshida
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan.
| | - Kouya Shiraishi
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Shigehiro Yagishita
- Division of Molecular Pharmacology, National Cancer Center Research Institute, Tokyo, Japan
| | - Hanako Ono
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yuji Uehara
- Division of Cancer Evolution, National Cancer Center Research Institute, Tokyo, Japan; Department of Thoracic Oncology and Respiratory Medicine, Tokyo Metropolitan Cancer and Infectious Diseases Center, Komagome Hospital, Tokyo, Japan
| | - Jun Miyakoshi
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Akiko Tateishi
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | | | | | - Akifumi Mochizuki
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Ken Masuda
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yuji Matsumoto
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yuki Shinno
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yusuke Okuma
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yasushi Goto
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Hidehito Horinouchi
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Ryuji Hamamoto
- Division of Medical AI Research and Development, National Cancer Center Research Institute, Tokyo, Japan
| | - Noboru Yamamoto
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan; Department of Experimental Therapeutics, National Cancer Center Hospital, Tokyo, Japan
| | - Shun-Ichi Watanabe
- Department of Thoracic Surgery, National Cancer Center Hospital, Tokyo, Japan
| | - Yasushi Yatabe
- Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan
| | - Kazuhisa Takahashi
- Department of Respiratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan
| | - Takashi Kohno
- Division of Genome Biology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yuichiro Ohe
- Department of Thoracic Oncology, National Cancer Center Hospital, Tokyo, Japan
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8
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Li L, Lyu H, Chen Q, Bai Y, Yu J, Cai R. Molecular Characteristics of Prognosis and Chemotherapy Response in Breast Cancer: Biomarker Identification Based on Gene Mutations and Pathway. J Breast Cancer 2025; 28:61-71. [PMID: 40133984 PMCID: PMC12046353 DOI: 10.4048/jbc.2024.0177] [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: 07/31/2024] [Revised: 11/18/2024] [Accepted: 12/16/2024] [Indexed: 03/27/2025] Open
Abstract
PURPOSE This study aimed to investigate the molecular characteristics associated with better prognosis in breast cancer. METHODS We performed targeted sequencing of 962 genes in 56 samples, categorizing them into long-term and short-term survival groups as well as chemotherapy-sensitive and chemotherapy-resistant groups for further analyses. RESULTS The results indicated that the tumor mutational burden values were significantly higher in the short-term survival and chemotherapy-resistant groups (p = 0.008 and p = 0.003, respectively). Somatic mutation analysis revealed that the mutation frequencies of BCL9L and WHSC1 were significantly lower in the long-term survival group than those in the short-term survival group (p = 0.029 and p = 0.024, respectively). CREB-regulated transcription coactivator 1 (CRTC1) mutations occurred significantly more frequently in the chemotherapy-resistant group (p = 0.027) and were associated with shorter progression-free survival (p = 0.036). Signature weighting analysis showed a significant increase in Signature.3, which is associated with homologous recombination repair deficiency in the chemotherapy-sensitive group (p = 0.045). Conversely, signatures related to effective DNA repair mechanisms, Signature.1 and Signature.15, were significantly reduced (p = 0.002 and p < 0.001, respectively). Kyoto Encyclopedia of Genes and Genomes pathway analysis indicated that gene mutations were significantly enriched in the JAK-STAT signaling pathway. CONCLUSION This study, through intergroup comparative analysis, found that immunotherapy (using programmed death 1/programmed death-ligand 1 inhibitors) may improve the prognosis of patients with short survival and chemotherapy resistance. Additionally, the study revealed that mutations in BCL9L and WHSC1 could serve as biomarkers for breast cancer prognosis, while CRTC1 mutations and Signature.3 could predict chemotherapy response. The study also found that the JAK-STAT pathway might be a potential therapeutic target for chemotherapy resistance. Therefore, this study identifies molecular characteristics that influence the prognosis of breast cancer patients, providing important theoretical insights for the development of personalized treatment strategies.
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Affiliation(s)
- Liyan Li
- Beijing Pinggu District Maternal and Child Health Care Hospital, Beijing, China
| | - Hongwei Lyu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China
| | | | | | - Jing Yu
- Cancer Center, Beijing Friendship Hospital, Capital Medical University, Beijing, China.
| | - Ruigang Cai
- Department of Medical Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
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Toor SM, Aldous EK, Parray A, Akhtar N, Al-Sarraj Y, Arredouani A, Pir GJ, Pananchikkal SV, El-Agnaf O, Shuaib A, Alajez NM, Albagha OM. Circulating PIWI-interacting RNAs in Acute Ischemic Stroke patients. Noncoding RNA Res 2025; 11:294-302. [PMID: 39926617 PMCID: PMC11802372 DOI: 10.1016/j.ncrna.2025.01.005] [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: 08/28/2024] [Revised: 01/13/2025] [Accepted: 01/14/2025] [Indexed: 02/11/2025] Open
Abstract
Background Stroke refers to an abrupt neurological deficit, caused by an acute focal injury of the central nervous system via infarction or hemorrhage due to impaired vascularity, and remains among the leading causes of disability and death worldwide. Stroke is often preceded by an episode of neuronal deficit termed transient ischemic attack (TIA), which presents an effective opportunity for mitigating the risk of an eminent acute ischemic stroke (AIS). Circulating non-coding RNAs (ncRNAs) have emerged as important biomarkers for stroke, but PIWI-interacting RNAs (piRNAs), a class of small regulatory ncRNAs, have not been previously explored as diagnostic or prognostic biomarkers for stroke. Methods We conducted comprehensive circulating piRNA profiling of AIS and TIA patients using RNA-seq on serum samples collected within 24 h of clinical diagnosis. The study cohort was divided into discovery and cross-validation datasets to identify replicated piRNAs using stringent analysis cut-offs. The expression levels of the panel of differentially regulated piRNAs between AIS and TIA patients were also compared with healthy controls. Results We identified a panel of 10 differentially regulated piRNAs between AIS and TIA patients; hsa-piR-28272, -piR-32972, -piR-28247, -piR-24553, -piR-24552, -piR-28275, -piR-28707 and -piR-32882 were upregulated, while hsa-piR-23058 and -piR-23136 were downregulated in AIS patients. Moreover, these 10 piRNAs were also differentially expressed in AIS patients compared to healthy controls. In addition, we investigated the potential gene targets of the dysregulated piRNAs and their plausible involvement in pathophysiological processes affected in stroke. Conclusions The imbalances in the circulating piRnome of AIS and TIA patients presented herein provide important insights into the roles of piRNAs following ischemic brain injury and potentially provide opportunities to mitigate stroke-induced mortality and morbidity.
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Affiliation(s)
- Salman M. Toor
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha, Qatar
| | - Eman K. Aldous
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha, Qatar
| | - Aijaz Parray
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation (HMC), P.O. Box 3050, Doha, Qatar
| | - Naveed Akhtar
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation (HMC), P.O. Box 3050, Doha, Qatar
- Department of Internal Medicine, University of Manitoba, MB R3A 1R9, Winnipeg, Canada
| | - Yasser Al-Sarraj
- Qatar Genome Program (QGP), Qatar Foundation Research, Development and Innovation, Qatar Foundation (QF), P.O. Box 5825, Doha, Qatar
| | - Abdelilah Arredouani
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha, Qatar
| | - Ghulam Jeelani Pir
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation (HMC), P.O. Box 3050, Doha, Qatar
| | - Sajitha V. Pananchikkal
- The Neuroscience Institute, Academic Health System, Hamad Medical Corporation (HMC), P.O. Box 3050, Doha, Qatar
| | - Omar El-Agnaf
- Neurological Disorders Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha, Qatar
| | - Ashfaq Shuaib
- Division of Neurology, Department of Medicine, University of Alberta, AB T6G 2R3, Edmonton, Canada
- Department of Neurology, Hamad Medical Corporation (HMC), P.O. Box 5825, Doha, Qatar
| | - Nehad M. Alajez
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha, Qatar
- Translational Oncology Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha, Qatar
| | - Omar M.E. Albagha
- College of Health and Life Sciences (CHLS), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha, Qatar
- Diabetes Research Center, Qatar Biomedical Research Institute (QBRI), Hamad Bin Khalifa University (HBKU), Qatar Foundation (QF), P.O. Box 34110, Doha, Qatar
- Centre for Genomic and Experimental Medicine, Institute of Genetics and Cancer, University of Edinburgh, EH4 2XU, Edinburgh, UK
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10
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Kempter T, Richter-Pechańska P, Michel K, Rausch T, Erarslan-Uysal B, Eckert C, Zimmermann M, Stanulla M, Schrappe M, Cario G, Köhrer S, Attarbaschi A, Korbel JO, Kunz JB, Kulozik AE. Subclonal TP53 and KRAS variants combined with poor treatment response identify ultrahigh-risk pediatric patients with T-ALL. Blood Adv 2025; 9:1267-1279. [PMID: 39808796 PMCID: PMC11950767 DOI: 10.1182/bloodadvances.2024014209] [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: 07/29/2024] [Revised: 10/28/2024] [Accepted: 11/14/2024] [Indexed: 01/16/2025] Open
Abstract
ABSTRACT Variations in the TP53 and KRAS genes indicate a particularly adverse prognosis in relapsed pediatric T-cell acute lymphoblastic leukemia (T-ALL). We hypothesized that these variations might be subclonally present at disease onset and contribute to relapse risk. To test this, we examined 2 cohorts of children diagnosed with T-ALL: cohort 1 with 81 patients who relapsed and 79 who matched nonrelapsing controls, and cohort 2 with 226 consecutive patients, 30 of whom relapsed. In cohort 1, targeted sequencing revealed TP53 clonal and subclonal variants in 6 of 81 relapsing patients but none in the nonrelapsing group (P = .014). KRAS alterations were found in 9 of 81 relapsing patients compared with 2 of 79 nonrelapsing patients (P = .032). Survival analysis showed that none of the relapsed patients with TP53 and/or KRAS alterations survived, whereas 19 of 67 relapsed patients without such variants did, with a minimum follow-up time of 3 years (P = .023). In cohort 2, none of the relapsing patients but 10 of 196 nonrelapsing patients carried TP53 or KRAS variants, indicating that mutation status alone does not predict poor prognosis. All 10 nonrelapsing patients with mutations had a favorable early treatment response. Among the total cohort of 386 patients, 188 showed poor treatment response, of whom 69 relapsed. Of these poor responders, 9 harbored TP53 or KRAS variants. In conclusion, subclonal TP53 and KRAS alterations identified at the time of initial diagnosis, along with a poor treatment response, characterize a subset of children with T-ALL who face a dismal prognosis and who may benefit from alternative treatment approaches.
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Affiliation(s)
- Tamara Kempter
- Department of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany
| | - Paulina Richter-Pechańska
- Department of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany
| | - Katarzyna Michel
- Department of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany
| | - Tobias Rausch
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany
- Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Büşra Erarslan-Uysal
- Department of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany
| | - Cornelia Eckert
- Department of Pediatric Oncology/Hematology, Charité University School of Medicine Berlin, Berlin, Germany
| | - Martin Zimmermann
- Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Martin Stanulla
- Pediatric Hematology and Oncology, Hannover Medical School, Hannover, Germany
| | - Martin Schrappe
- Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Gunnar Cario
- Department of Pediatrics, University Hospital Schleswig-Holstein, Campus Kiel, Kiel, Germany
| | - Stefan Köhrer
- Labdia Labordiagnostik, Vienna, Austria
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
| | - Andishe Attarbaschi
- St. Anna Children’s Cancer Research Institute, Vienna, Austria
- Department of Pediatric Hematology and Oncology, St. Anna Children’s Hospital, Medical University of Vienna, Vienna, Austria
| | - Jan O. Korbel
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany
- Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
- Bridging Research Division on Mechanisms of Genomic Variation and Data Science, German Cancer Research Center, Heidelberg, Germany
| | - Joachim B. Kunz
- Department of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany
| | - Andreas E. Kulozik
- Department of Pediatric Oncology, Hematology, and Immunology and Hopp Children’s Cancer Center Heidelberg, University of Heidelberg, Heidelberg, Germany
- Molecular Medicine Partnership Unit, European Molecular Biology Laboratory, University of Heidelberg, Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Leukemia, German Cancer Research Center, Heidelberg, Germany
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11
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Yang P, Gu H, Wu X, Chen G, Liu H, Chen Z. Tumour protein p53-activated lncRNA PGM5-AS1 suppresses lung cancer growth and stemness by targeting R-spondin1 via microRNA-1247-5p. Arch Physiol Biochem 2025:1-13. [PMID: 40035308 DOI: 10.1080/13813455.2025.2459318] [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: 06/20/2024] [Revised: 11/06/2024] [Accepted: 01/22/2025] [Indexed: 03/05/2025]
Abstract
OBJECTIVE This study was to investigated the inhibitory role of the tumour protein p53 (TP53)-activated PGM5-AS1 in lung cancer (LC) cell proliferation, invasion, and CSC-like properties and its underlying mechanisms. METHODS The effect of PGM5-AS1 on LC cell development was determined. Stem cell markers, aldehyde dehydrogenase activity in cells were tested, as well as the ability of stem cells to form spheroids. The interaction of PGM5-AS1 and TP53 was determined. The binding link of PGM5-AS1, miR-1247-5p, and R-spondin1 (RSPO1) was verified. RESULTS PGM5-AS1 was elevated by a combination of TP53 and PGM5-AS1 promoters. PGM5-AS1 was a molecular sponge of miR-1247-5p in LC cells, and miR-1247-5p targeted RSPO1. Elevating PGM5-AS1 or repressing miR-1247-5p restrained LC cell growth and stemness, which were reversed by depression of RSPO1. CONCLUSION This study conveys that TP53-elevated PGM5-AS1 mediates miR-1247-5p to target RSPO1, thereby inhibiting LC growth and stemness, representing a novel avenue for LC therapy.
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Affiliation(s)
- Peng Yang
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Hong Gu
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Xuanqin Wu
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Geng Chen
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Heng Liu
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
| | - Zhongliang Chen
- Department of Cardiothoracic and Vascular Surgery, Shenzhen Guangming District People's Hospital, Shenzhen, Guangdong, China
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12
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Yang H, Zhang L, Kang X, Si Y, Song P, Su X. Reaction Pathway Differentiation Enabled Fingerprinting Signal for Single Nucleotide Variant Detection. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2025; 12:e2412680. [PMID: 39903775 PMCID: PMC11948007 DOI: 10.1002/advs.202412680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/10/2024] [Revised: 01/17/2025] [Indexed: 02/06/2025]
Abstract
Accurate identification of single-nucleotide variants (SNVs) is paramount for disease diagnosis. Despite the facile design of DNA hybridization probes, their limited specificity poses challenges in clinical applications. Here, a differential reaction pathway probe (DRPP) based on a dynamic DNA reaction network is presented. DRPP leverages differences in reaction intermediate concentrations between SNV and WT groups, directing them into distinct reaction pathways. This generates a strong pulse-like signal for SNV and a weak unidirectional increase signal for wild-type (WT). Through the application of machine learning to fluorescence kinetic data analysis, the classification of SNV and WT signals is automated with an accuracy of 99.6%, significantly exceeding the 80.7% accuracy of conventional methods. Additionally, sensitivity for variant allele frequency (VAF) is enhanced down to 0.1%, representing a ten-fold improvement over conventional approaches. DRPP accurately identified D614G and N501Y SNVs in the S gene of SARS-CoV-2 variants in patient swab samples with accuracy over 99% (n = 82). It determined the VAF of ovarian cancer-related mutations KRAS-G12R, NRAS-G12C, and BRAF-V600E in both tissue and blood samples (n = 77), discriminating cancer patients and healthy individuals with significant difference (p < 0.001). The potential integration of DRPP into clinical diagnostics, along with rapid amplification techniques, holds promise for early disease diagnostics and personalized diagnostics.
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Affiliation(s)
- Huixiao Yang
- State Key Laboratory of Organic‐Inorganic CompositesBeijing Key Laboratory of BioprocessBeijing Advanced Innovation Center for Soft Matter Science and EngineeringCollege of Life Science and TechnologyBeijing University of Chemical TechnologyBeijing100029China
| | - Linghao Zhang
- State Key Laboratory of Organic‐Inorganic CompositesBeijing Key Laboratory of BioprocessBeijing Advanced Innovation Center for Soft Matter Science and EngineeringCollege of Life Science and TechnologyBeijing University of Chemical TechnologyBeijing100029China
| | - Xinmiao Kang
- State Key Laboratory of Organic‐Inorganic CompositesBeijing Key Laboratory of BioprocessBeijing Advanced Innovation Center for Soft Matter Science and EngineeringCollege of Life Science and TechnologyBeijing University of Chemical TechnologyBeijing100029China
| | - Yunpei Si
- School of Biomedical EngineeringZhangjiang Institute for Advanced Study and National Center for Translational MedicineShanghai Jiao Tong UniversityShanghai200240China
| | - Ping Song
- School of Biomedical EngineeringZhangjiang Institute for Advanced Study and National Center for Translational MedicineShanghai Jiao Tong UniversityShanghai200240China
| | - Xin Su
- State Key Laboratory of Organic‐Inorganic CompositesBeijing Key Laboratory of BioprocessBeijing Advanced Innovation Center for Soft Matter Science and EngineeringCollege of Life Science and TechnologyBeijing University of Chemical TechnologyBeijing100029China
- State Key Laboratory of Natural and Biomimetic DrugsPeking UniversityBeijing100191China
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13
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Müller M, May S, Hall H, Kendall TJ, McGarry L, Blukacz L, Nuciforo S, Georgakopoulou A, Jamieson T, Phinichkusolchit N, Dhayade S, Suzuki T, Huguet-Pradell J, Powley IR, Officer-Jones L, Pennie RL, Esteban-Fabró R, Gris-Oliver A, Pinyol R, Skalka GL, Leslie J, Hoare M, Sprangers J, Malviya G, Mackintosh A, Johnson E, McCain M, Halpin J, Kiourtis C, Nixon C, Clark G, Clark W, Shaw R, Hedley A, Drake TM, Tan EH, Neilson M, Murphy DJ, Lewis DY, Reeves HL, Le Quesne J, Mann DA, Carlin LM, Blyth K, Llovet JM, Heim MH, Sansom OJ, Miller CJ, Bird TG. Human-correlated genetic models identify precision therapy for liver cancer. Nature 2025; 639:754-764. [PMID: 39972137 PMCID: PMC11922762 DOI: 10.1038/s41586-025-08585-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: 05/09/2022] [Accepted: 01/02/2025] [Indexed: 02/21/2025]
Abstract
Hepatocellular carcinoma (HCC), the most common form of primary liver cancer, is a leading cause of cancer-related mortality worldwide1,2. HCC occurs typically from a background of chronic liver disease, caused by a spectrum of predisposing conditions. Tumour development is driven by the expansion of clones that accumulate progressive driver mutations3, with hepatocytes the most likely cell of origin2. However, the landscape of driver mutations in HCC is broadly independent of the underlying aetiologies4. Despite an increasing range of systemic treatment options for advanced HCC, outcomes remain heterogeneous and typically poor. Emerging data suggest that drug efficacies depend on disease aetiology and genetic alterations5,6. Exploring subtypes in preclinical models with human relevance will therefore be essential to advance precision medicine in HCC7. Here we generated a suite of genetically driven immunocompetent in vivo and matched in vitro HCC models. Our models represent multiple features of human HCC, including clonal origin, histopathological appearance and metastasis. We integrated transcriptomic data from the mouse models with human HCC data and identified four common human-mouse subtype clusters. The subtype clusters had distinct transcriptomic characteristics that aligned with the human histopathology. In a proof-of-principle analysis, we verified response to standard-of-care treatment and used a linked in vitro-in vivo pipeline to identify a promising therapeutic candidate, cladribine, that has not previously been linked to HCC treatment. Cladribine acts in a highly effective subtype-specific manner in combination with standard-of-care therapy.
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Affiliation(s)
| | - Stephanie May
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Holly Hall
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Timothy J Kendall
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Lynn McGarry
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Lauriane Blukacz
- Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
| | - Sandro Nuciforo
- Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
| | - Anastasia Georgakopoulou
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | - Narisa Phinichkusolchit
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | | | | | - Júlia Huguet-Pradell
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Ian R Powley
- Cancer Research UK Scotland Institute, Glasgow, UK
| | | | | | - Roger Esteban-Fabró
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Albert Gris-Oliver
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | - Roser Pinyol
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
| | | | - Jack Leslie
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - Matthew Hoare
- Early Cancer Institute, University of Cambridge, Cambridge, UK
- Department of Medicine, University of Cambridge, Addenbrooke's Hospital, Cambridge, UK
| | | | | | | | - Emma Johnson
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Misti McCain
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
| | - John Halpin
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Christos Kiourtis
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Colin Nixon
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Graeme Clark
- Cancer Research UK Scotland Institute, Glasgow, UK
| | | | - Robin Shaw
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Ann Hedley
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Thomas M Drake
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Centre for Medical Informatics, Usher Institute, University of Edinburgh, Edinburgh, UK
| | - Ee Hong Tan
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Matt Neilson
- Cancer Research UK Scotland Institute, Glasgow, UK
| | - Daniel J Murphy
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - David Y Lewis
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Helen L Reeves
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- Liver Group, Newcastle-upon-Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK
| | - John Le Quesne
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Department of Histopathology, Queen Elizabeth University Hospital, Glasgow, UK
| | - Derek A Mann
- Newcastle Fibrosis Research Group, Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK
- The Newcastle University Centre for Cancer, Newcastle University, Newcastle upon Tyne, UK
- Department of Gastroenterology and Hepatology, School of Medicine, Koç University, Istanbul, Turkey
| | - Leo M Carlin
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Karen Blyth
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Josep M Llovet
- Liver Cancer Translational Research Group, Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic, Universitat de Barcelona, Barcelona, Spain
- Mount Sinai Liver Cancer Program, Division of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
- Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Markus H Heim
- Department of Biomedicine, University Hospital and University of Basel, Basel, Switzerland
- University Digestive Health Care Center Basel-Clarunis, Basel, Switzerland
| | - Owen J Sansom
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
- Cancer Research UK Scotland Centre, Edinburgh, UK
- Cancer Research UK Scotland Centre, Glasgow, UK
| | - Crispin J Miller
- Cancer Research UK Scotland Institute, Glasgow, UK
- School of Cancer Sciences, University of Glasgow, Glasgow, UK
| | - Thomas G Bird
- Cancer Research UK Scotland Institute, Glasgow, UK.
- School of Cancer Sciences, University of Glasgow, Glasgow, UK.
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK.
- Cancer Research UK Scotland Centre, Edinburgh, UK.
- Cancer Research UK Scotland Centre, Glasgow, UK.
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14
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Rinaldi R, Laurino S, Salvia R, Russi S, De Stefano F, Galasso R, Sgambato A, Scieuzo C, Falco G, Falabella P. Biological Activity of Peptide Fraction Derived from Hermetia illucens L. (Diptera: Stratiomyidae) Larvae Haemolymph on Gastric Cancer Cells. Int J Mol Sci 2025; 26:1885. [PMID: 40076512 PMCID: PMC11899352 DOI: 10.3390/ijms26051885] [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: 01/21/2025] [Revised: 02/15/2025] [Accepted: 02/19/2025] [Indexed: 03/14/2025] Open
Abstract
Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide, characterised by poor prognosis and limited responsiveness to chemotherapy. There is a need for new and more effective anticancer agents. Antimicrobial peptides (AMPs) represent a promising class of biomolecules for this purpose. Naturally occurring in the innate immune system, these peptides can also exert cytotoxic effects against cancer cells, earning them the designation of "anticancer peptides" (ACPs). They have the potential to be a viable support for current chemotherapy schedules due to their selectivity against cancer cells and minor propensity to induce chemoresistance in cells. Insects are an excellent source of AMPs. Among them, due to its ability to thrive in hostile and microorganism-rich environments, we isolated a peptide fraction from Hermetia illucens L. (Diptera: Stratiomyidae) haemolymph to evaluate a possible anticancer activity. We tested Peptide Fractions (PFs) against AGS and KATO III gastric cancer cell lines. Data obtained indicated that PFs, especially those resulting from Escherichia coli and Micrococcus flavus infection (to boost immune response), were able to inhibit tumour cell growth by inducing apoptosis or cell cycle arrest in a cell line-specific manner. These results support further investigation into the use of antimicrobial peptides produced from insects as possible anticancer agents.
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Affiliation(s)
- Roberta Rinaldi
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
| | - Simona Laurino
- Centro di Riferimento Oncologico della Basilicata IRCCS (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (S.L.); (S.R.); (R.G.)
| | - Rosanna Salvia
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
- Spinoff XFlies S.R.L, University of Basilicata, Via Dell’Ateneo Lucano 10, 85100 Potenza, Italy
| | - Sabino Russi
- Centro di Riferimento Oncologico della Basilicata IRCCS (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (S.L.); (S.R.); (R.G.)
| | - Federica De Stefano
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
| | - Rocco Galasso
- Centro di Riferimento Oncologico della Basilicata IRCCS (IRCCS-CROB), 85028 Rionero in Vulture, Italy; (S.L.); (S.R.); (R.G.)
| | - Alessandro Sgambato
- Department of Translational Medicine and Surgery, Università Cattolica del Sacro Cuore, 00168 Rome, Italy;
- Multiplex Spatial Profiling Facility, Fondazione Policlinico Universitario ‘Agostino Gemelli’ IRCCS, 00136 Rome, Italy
| | - Carmen Scieuzo
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
- Spinoff XFlies S.R.L, University of Basilicata, Via Dell’Ateneo Lucano 10, 85100 Potenza, Italy
| | - Geppino Falco
- Department of Biology, University of Naples Federico II, 80126 Naples, Italy;
| | - Patrizia Falabella
- Department of Basic and Applied Sciences, University of Basilicata, Via dell’Ateneo Lucano 10, 85100 Potenza, Italy; (R.R.); (R.S.); (F.D.S.)
- Spinoff XFlies S.R.L, University of Basilicata, Via Dell’Ateneo Lucano 10, 85100 Potenza, Italy
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15
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Liu J, Shen Y, Liu J, Xu D, Chang CY, Wang J, Zhou J, Haffty BG, Zhang L, Bargonetti J, De S, Hu W, Feng Z. Lipogenic enzyme FASN promotes mutant p53 accumulation and gain-of-function through palmitoylation. Nat Commun 2025; 16:1762. [PMID: 39971971 PMCID: PMC11839913 DOI: 10.1038/s41467-025-57099-9] [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: 09/23/2023] [Accepted: 02/11/2025] [Indexed: 02/21/2025] Open
Abstract
The tumor-suppressive function of p53 is frequently disrupted by mutations in cancers. Missense mutant p53 (mutp53) protein often stabilizes and accumulates to high levels in cancers to promote tumorigenesis through the gain-of-function (GOF) mechanism. Currently, the mechanism of mutp53 accumulation and GOF is incompletely understood. Here, we identify the lipogenic enzyme FASN as an important regulator of mutp53 accumulation and GOF. FASN interacts with mutp53 to enhance mutp53 palmitoylation, which inhibits mutp53 ubiquitination to promote mutp53 accumulation and GOF. Blocking FASN genetically or by small-molecule inhibitors suppresses mutp53 palmitoylation to inhibit mutp53 accumulation, which in turn inhibits the growth of mutp53 tumors in orthotopic and subcutaneous xenograft tumor models and transgenic mice, as well as the growth of human tumor organoids carrying mutp53. Our results reveal that mutp53 palmitoylation is an important mechanism underlying mutp53 accumulation and GOF, and targeting FASN is a potential therapeutic strategy for cancers carrying mutp53.
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Affiliation(s)
- Juan Liu
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA
| | - Yiyun Shen
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA
| | - Jie Liu
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA
| | - Dandan Xu
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA
| | - Chun-Yuan Chang
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA
| | - Jianming Wang
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA
| | - Jason Zhou
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA
| | - Bruce G Haffty
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA
| | - Lanjing Zhang
- Department of Pathology, Princeton Medical Center, Princeton, NJ, USA
- Department of Cell Biology and Neuroscience, Rutgers-State University of New Jersey, Piscataway, NJ, USA
| | - Jill Bargonetti
- Department of Biological Sciences, Hunter College, City University of New York, New York, NY, USA
| | - Subhajyoti De
- Center for Systems and Computational Biology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA
| | - Wenwei Hu
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA.
| | - Zhaohui Feng
- Department of Radiation Oncology, Rutgers Cancer Institute, Rutgers-State University of New Jersey, New Brunswick, NJ, USA.
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16
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Hertel A, Storchová Z. The Role of p53 Mutations in Early and Late Response to Mitotic Aberrations. Biomolecules 2025; 15:244. [PMID: 40001547 PMCID: PMC11852650 DOI: 10.3390/biom15020244] [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: 12/20/2024] [Revised: 01/30/2025] [Accepted: 02/01/2025] [Indexed: 02/27/2025] Open
Abstract
Mutations in the TP53 gene and chromosomal instability (CIN) are two of the most common alterations in cancer. CIN, marked by changes in chromosome numbers and structure, drives tumor development, but is poorly tolerated in healthy cells, where developmental and tissue homeostasis mechanisms typically eliminate cells with chromosomal abnormalities. Mechanisms that allow cancer cells to acquire and adapt to CIN remain largely unknown. Tumor suppressor protein p53, often referred to as the "guardian of the genome", plays a critical role in maintaining genomic stability. In cancer, CIN strongly correlates with TP53 mutations, and recent studies suggest that p53 prevents the propagation of cells with abnormal karyotypes arising from mitotic errors. Furthermore, p53 dysfunction is frequent in cells that underwent whole-genome doubling (WGD), a process that facilitates CIN onset, promotes aneuploidy tolerance, and is associated with poor patient prognosis across multiple cancer types. This review summarizes current insights into p53's role in protecting cells from chromosome copy number alterations and discusses the implications of its dysfunction for the adaption and propagation of cancer cells.
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Affiliation(s)
| | - Zuzana Storchová
- Group Molecular Genetics, Faculty of Biology, RPTU Kaiserslautern-Landau, Paul Ehrlich Str. 24, 67663 Kaiserslautern, Germany
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17
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Zucker M, Perry MA, Gould SI, Elkrief A, Safonov A, Thummalapalli R, Mehine M, Chakravarty D, Brannon AR, Ladanyi M, Razavi P, Donoghue MTA, Murciano-Goroff YR, Grigoriadis K, McGranahan N, Jamal-Hanjani M, Swanton C, Chen Y, Shen R, Chandarlapaty S, Solit DB, Schultz N, Berger MF, Chang J, Schoenfeld AJ, Sánchez-Rivera FJ, Reznik E, Bandlamudi C. Pan-cancer analysis of biallelic inactivation in tumor suppressor genes identifies KEAP1 zygosity as a predictive biomarker in lung cancer. Cell 2025; 188:851-867.e17. [PMID: 39701102 PMCID: PMC11922039 DOI: 10.1016/j.cell.2024.11.010] [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: 11/03/2023] [Revised: 08/14/2024] [Accepted: 11/10/2024] [Indexed: 12/21/2024]
Abstract
The canonical model of tumor suppressor gene (TSG)-mediated oncogenesis posits that loss of both alleles is necessary for inactivation. Here, through allele-specific analysis of sequencing data from 48,179 cancer patients, we define the prevalence, selective pressure for, and functional consequences of biallelic inactivation across TSGs. TSGs largely assort into distinct classes associated with either pan-cancer (Class 1) or lineage-specific (Class 2) patterns of selection for biallelic loss, although some TSGs are predominantly monoallelically inactivated (Class 3/4). We demonstrate that selection for biallelic inactivation can be utilized to identify driver genes in non-canonical contexts, including among variants of unknown significance (VUSs) of several TSGs such as KEAP1. Genomic, functional, and clinical data collectively indicate that KEAP1 VUSs phenocopy established KEAP1 oncogenic alleles and that zygosity, rather than variant classification, is predictive of therapeutic response. TSG zygosity is therefore a fundamental determinant of disease etiology and therapeutic sensitivity.
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Affiliation(s)
- Mark Zucker
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Maria A Perry
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Samuel I Gould
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Arielle Elkrief
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Anton Safonov
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Rohit Thummalapalli
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Miika Mehine
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Debyani Chakravarty
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - A Rose Brannon
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Marc Ladanyi
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Pedram Razavi
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Mark T A Donoghue
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Kristiana Grigoriadis
- Cancer Evolution and Genome Instability Laboratory, The Francis Crick Institute, London, UK; Cancer Research UK Lung Cancer Centre of Excellence, University College London, London, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK
| | - Nicholas McGranahan
- Cancer Research UK Lung Cancer Centre of Excellence, University College London, London, UK; Cancer Genome Evolution Research Group, University College London Cancer Institute, London, UK
| | - Mariam Jamal-Hanjani
- Cancer Research UK Lung Cancer Centre of Excellence, University College London, London, UK; Cancer Metastasis Laboratory, University College London Cancer Institute, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK
| | - 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, London, UK; Department of Medical Oncology, University College London Hospitals, London, UK
| | - Yuan Chen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Ronglai Shen
- Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Sarat Chandarlapaty
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - David B Solit
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nikolaus Schultz
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA
| | - Michael F Berger
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Weill Cornell Medical College, New York, NY, USA
| | - Jason Chang
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Adam J Schoenfeld
- Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Francisco J Sánchez-Rivera
- Department of Biology, Massachusetts Institute of Technology, Cambridge, MA, USA; David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, USA
| | - Ed Reznik
- Computational Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
| | - Chaitanya Bandlamudi
- Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
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18
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Bora Yildiz C, Du J, Mohan KN, Zimmer-Bensch G, Abdolahi S. The role of lncRNAs in the interplay of signaling pathways and epigenetic mechanisms in glioma. Epigenomics 2025; 17:125-140. [PMID: 39829063 PMCID: PMC11792803 DOI: 10.1080/17501911.2024.2442297] [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: 05/13/2024] [Accepted: 12/10/2024] [Indexed: 01/22/2025] Open
Abstract
Gliomas, highly aggressive tumors of the central nervous system, present overwhelming challenges due to their heterogeneity and therapeutic resistance. Glioblastoma multiforme (GBM), the most malignant form, underscores this clinical urgency due to dismal prognosis despite aggressive treatment regimens. Recent advances in cancer research revealed signaling pathways and epigenetic mechanisms that intricately govern glioma progression, offering multifaceted targets for therapeutic intervention. This review explores the dynamic interplay between signaling events and epigenetic regulation in the context of glioma, with a particular focus on the crucial roles played by non-coding RNAs (ncRNAs). Through direct and indirect epigenetic targeting, ncRNAs emerge as key regulators shaping the molecular landscape of glioblastoma across its various stages. By dissecting these intricate regulatory networks, novel and patient-tailored therapeutic strategies could be devised to improve patient outcomes with this devastating disease.
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Affiliation(s)
- Can Bora Yildiz
- Division of Neuroepigenetics, Institute of Zoology (Biology 2), RWTH Aachen University, Aachen, Germany
- Research Training Group 2416 Multi Senses – Multi Scales, RWTH Aachen University, Aachen, Germany
| | - Jian Du
- Division of Neuroepigenetics, Institute of Zoology (Biology 2), RWTH Aachen University, Aachen, Germany
| | - K. Naga Mohan
- Molecular Biology and Genetics Laboratory, Department of Biological Sciences, Hyderabad, India
| | - Geraldine Zimmer-Bensch
- Division of Neuroepigenetics, Institute of Zoology (Biology 2), RWTH Aachen University, Aachen, Germany
- Research Training Group 2416 Multi Senses – Multi Scales, RWTH Aachen University, Aachen, Germany
| | - Sara Abdolahi
- Division of Neuroepigenetics, Institute of Zoology (Biology 2), RWTH Aachen University, Aachen, Germany
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19
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Joerger AC, Stiewe T, Soussi T. TP53: the unluckiest of genes? Cell Death Differ 2025; 32:219-224. [PMID: 39443700 PMCID: PMC11803090 DOI: 10.1038/s41418-024-01391-6] [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: 05/10/2024] [Revised: 09/22/2024] [Accepted: 09/27/2024] [Indexed: 10/25/2024] Open
Abstract
The transcription factor p53 plays a key role in the cellular defense against cancer development. It is inactivated in virtually every tumor, and in every second tumor this inactivation is due to a mutation in the TP53 gene. In this perspective, we show that this diverse mutational spectrum is unique among all other cancer-associated proteins and discuss what drives the selection of TP53 mutations in cancer. We highlight that several factors conspire to make the p53 protein particularly vulnerable to inactivation by the mutations that constantly plague our genome. It appears that the TP53 gene has emerged as a victim of its own evolutionary past that shaped its structure and function towards a pluripotent tumor suppressor, but came with an increased structural fragility of its DNA-binding domain. TP53 loss of function - with associated dominant-negative effects - is the main mechanism that will impair TP53 tumor suppressive function, regardless of whether a neomorphic phenotype is associated with some of these variants.
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Affiliation(s)
- Andreas C Joerger
- Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt am Main, Germany.
- Structural Genomics Consortium (SGC), Buchmann Institute for Molecular Life Sciences, Frankfurt am Main, Germany.
| | - Thorsten Stiewe
- Institute of Molecular Oncology, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Philipps University, Marburg, Germany.
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany.
| | - Thierry Soussi
- Equipe « Hematopoietic and Leukemic Development », Sorbonne Université, INSERM, Centre de Recherche Saint-Antoine, CRSA, AP-HP, SIRIC CURAMUS, Paris, France.
- Dept. of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden.
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20
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Aswathy R, Suganya K, Varghese CA, Sumathi S. Deciphering the Expression, Functional Role, and Prognostic Significance of P53 in Cervical Cancer Through Bioinformatics Analysis. J Obstet Gynaecol India 2025; 75:36-45. [PMID: 40092388 PMCID: PMC11904074 DOI: 10.1007/s13224-024-01954-0] [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: 09/22/2023] [Accepted: 01/13/2024] [Indexed: 03/19/2025] Open
Abstract
Background Cervical cancer (CC) poses a persistent global health challenge, and it increases the mortality risk among women. P53 gene plays a pivotal role in CC regulation; yet, a comprehensive exploration of its expression levels and prognostic relevance is not fully understood. Aim The aim of this research was to utilize bioinformatics analysis on publicly available patient data to investigate and understand the expression patterns of the TP53 gene in CC. Materials and Methods The study utilizes the TIMER 2.0 and UALCAN databases to assess TP53 expression and its relationship with immune cell infiltration in CC. Additionally, genetic alterations in TP53 are explored using the cBioPortal database. Functional enrichment analysis unveils the molecular processes associated with TP53. Kaplan-Meier analysis examines TP53 prognostic significance. Results The study reveals that TP53 expression is significantly up regulated in CC, potentially driven by genetic alterations. TP53 expression positively correlates with immune cell infiltration, including CD8 + T cells, CD4 + T cells, neutrophils, and macrophages, suggesting its role in shaping the tumor microenvironment. Functional analysis identifies TP53 involvement in essential cellular processes, including chromatin assembly, DNA conformation change, and carbohydrate kinase activity. Kaplan-Meier analysis highlights the prognostic significance of TP53, showing a poorer overall survival in CC patients with high TP53 expression. Conclusion The results underscore the prognostic potential of P53 in CC and its utility as a biomarker for assessing prognosis associated to tumor-immune infiltration. This study provides valuable insights into the multifaceted role of P53 in cervical carcinogenesis and its implications for therapeutic interventions and personalized medicine.
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Affiliation(s)
- Raghu Aswathy
- Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu 641 043 India
| | - Kanagaraj Suganya
- Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu 641 043 India
| | - Chalos Angel Varghese
- Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu 641 043 India
| | - Sundaravadivelu Sumathi
- Department of Biochemistry, Biotechnology and Bioinformatics, Avinashilingam Institute for Home Science and Higher Education for Women, Coimbatore, Tamil Nadu 641 043 India
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21
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Lacka K, Maciejewski A, Tyburski P, Manuszewska-Jopek E, Majewski P, Więckowska B. Rationale for Testing TP53 Mutations in Thyroid Cancer-Original Data and Meta-Analysis. Int J Mol Sci 2025; 26:1035. [PMID: 39940804 PMCID: PMC11817394 DOI: 10.3390/ijms26031035] [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: 11/27/2024] [Revised: 01/15/2025] [Accepted: 01/21/2025] [Indexed: 02/16/2025] Open
Abstract
The p53 protein is a tumor-suppressing transcription factor that is critical in tumorigenesis. While TP53 mutations are rare in differentiated thyroid cancer (DTC), they are significantly more common in anaplastic thyroid cancer (ATC). This study presents original results and a meta-analysis reevaluating the prognostic value of TP53 mutations in thyroid cancer, including surrogate markers such as immunohistochemical p53 expression and serum p53-Abs levels. TP53 mutations were analyzed using SSSP and direct sequencing in a DTC group (15 patients), an ATC group (3 patients), and a control group (25 patients). The immunohistochemical p53 expression was assessed in tissue samples. A meta-analysis of 14 eligible studies identified through the PubMed, Scopus, Google Scholar, and Cochrane databases was conducted. Our results showed TP53 mutations in all ATC cases, 6.67% of DTC cases (1 out of 15), and none in the control group. Immunohistochemical p53 overexpression was observed in 4 out of 15 DTC (26.67%) and all ATC cases but absent in controls. A meta-analysis confirmed that TP53 mutations are significantly more frequent in ATC than controls (OR 8.95; 95% CI: 1.36-58.70; p = 0.02) but not in DTC vs. controls (OR 1.87; 95% CI: 0.53-6.58; p = 0.33). p53 overexpression was significantly higher in both DTC and ATC vs. controls (OR 7.99; 95% CI: 5.11-12.51; p < 0.01 and OR 64.37; 95% CI: 27.28-151.89; p < 0.01, respectively). The serum p53-Abs positivity was also elevated in patients with PTC vs. controls (OR 2.07; 95% CI: 1.24-3.47; p < 0.01). TP53 mutations are frequent events in the pathogenesis of ATC. In DTC, further prospective studies are needed to determine the prognostic value of TP53 mutations and related surrogate markers (immunohistochemical p53 expression, p53-Abs positivity).
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Affiliation(s)
- Katarzyna Lacka
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznan, Poland
| | - Adam Maciejewski
- Department of Endocrinology, Metabolism and Internal Medicine, Poznan University of Medical Sciences, 60-355 Poznan, Poland
| | - Piotr Tyburski
- Student Scientific Society, Poznan University of Medical Sciences, 60-806 Poznan, Poland
| | | | - Przemysław Majewski
- Department of Clinical Pathomorphology, Poznan University of Medical Sciences, 60-355 Poznan, Poland
| | - Barbara Więckowska
- Department of Computer Science and Statistics, Poznan University of Medical Science, 60-806 Poznan, Poland
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22
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Wu F, Zhang H, Hao M. Interactions between key genes and pathways in prostate cancer progression and therapy resistance. Front Oncol 2025; 15:1467540. [PMID: 39917165 PMCID: PMC11799259 DOI: 10.3389/fonc.2025.1467540] [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: 07/20/2024] [Accepted: 01/06/2025] [Indexed: 02/09/2025] Open
Abstract
Prostate cancer is one of the most prevalent malignant tumors in men, particularly in regions with a high Human Development Index. While the long-term survival rate for localized prostate cancer is relatively high, the mortality rate remains significantly elevated once the disease progresses to advanced stages, even with various intensive treatment modalities. The primary obstacle to curing advanced prostate cancer is the absence of comprehensive treatment strategies that effectively target the highly heterogeneous tumors at both genetic and molecular levels. Prostate cancer development is a complex, multigenic, and multistep process that involves numerous gene mutations, alteration in gene expression, and changes in signaling pathways. Key genetic and pathway alterations include the amplification and/or mutation of the androgen receptor, the loss of Rb, PTEN, and p53, the activation of the WNT signaling pathway, and the amplification of the MYC oncogene. This review summarizes the mechanisms by which these genes influence the progression of prostate cancer and highlights the interactions between multiple genes and their relationship with prostate cancer. Additionally, we reviewed the current state of treatments targeting these genes and signaling pathways, providing a comprehensive overview of therapeutic approaches in the context of prostate cancer.
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Affiliation(s)
- Fan Wu
- Department of Pathology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Hengsen Zhang
- Department of Neurosurgery, Affiliated Hospital of Jiangnan University, Wuxi, China
| | - Miaomiao Hao
- Department of Pathology, Shanghai Ninth People’s Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
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23
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Zhang B, Zhang H, Qin Y. A Primer on the Role of TP53 Mutation and Targeted Therapy in Endometrial Cancer. FRONT BIOSCI-LANDMRK 2025; 30:25447. [PMID: 39862074 DOI: 10.31083/fbl25447] [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: 06/30/2024] [Revised: 08/26/2024] [Accepted: 09/03/2024] [Indexed: 01/27/2025]
Abstract
Endometrial Cancer (EC) is one of the most common gynecological malignancies, ranking first in developed countries and regions. The occurrence and development of EC is closely associated with genetic mutations. TP53 mutation, in particular, can lead to the dysfunction of numerous regulatory factors and alteration of the tumor microenvironment (TME). The changes in the TME subsequently promote the development of tumors and assist in immune escape by tumor cells, making it more challenging to treat EC and resulting in a poor prognosis. Therefore, it is important to understand the effects of TP53 mutation in EC and to conduct further research in relation to the targeting of TP53 mutations. This article reviews current research progress on the role of TP53 mutations in regulating the TME and in the mechanism of EC tumorigenesis, as well as progress on drugs that target TP53 mutations.
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Affiliation(s)
- Bohao Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou Hospital of Zhengzhou University, 450000 Zhengzhou, Henan, China
| | - Haozhe Zhang
- Department of Oncology, The First Affiliated Hospital of Zhengzhou Hospital of Zhengzhou University, 450000 Zhengzhou, Henan, China
| | - Yanru Qin
- Department of Oncology, The First Affiliated Hospital of Zhengzhou Hospital of Zhengzhou University, 450000 Zhengzhou, Henan, China
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24
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XIA LIANGJIANG, LI GUANGBIN, ZHOU QINGWU, FENG YU, MA HAITAO. CircRNA circ_0015278 induces ferroptosis in lung adenocarcinoma through the miR-1228/P53 axis. Oncol Res 2025; 33:465-475. [PMID: 39866239 PMCID: PMC11753987 DOI: 10.32604/or.2024.050835] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Accepted: 05/11/2024] [Indexed: 01/28/2025] Open
Abstract
Background Circular RNAs play an important role in regulating lung adenocarcinoma (LUAD). Bioinformatics analysis identified circ_0015278 as differentially expressed in LUAD. However, the biological mechanism of circ_0015278 in LUAD has not been fully clarified, especially in ferroptosis. Materials and Methods Bioinformatics analysis was employed to explore the downstream mechanisms of Circ_0015278, subsequently confirmed by luciferase reporter assays. The impact of Circ_0015278 on cell proliferation, migration, invasion, and ferroptosis was investigated through a loss-of-function experiment. A xenotransplantation mouse model elucidated the effect of Circ_0015278 on tumour growth. Results Circ_0015278 exhibited downregulation in LUAD. It inhibited cell proliferation, migration, and invasion while promoting ferroptosis by interacting with miR-1228 to regulate P53 expression through a competitive endogenous RNA mechanism. Moreover, circ_0015278 suppressed tumour growth in mice. Conclusions Circ_0015278 was identified as a novel factor promoting ferroptosis in LUAD. Furthermore, it suppressed the malignant progression of LUAD through the miR-1228/P53 axis.
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Affiliation(s)
- LIANGJIANG XIA
- Department of Thoracic Surgery, The Fourth Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - GUANGBIN LI
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - QINGWU ZHOU
- The First Clinical Medical College of Nanchang University, The First Affiliated Hospital of Nanchang University, Nanchang, 330006, China
| | - YU FENG
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
| | - HAITAO MA
- Department of Thoracic Surgery, The First Affiliated Hospital of Soochow University, Suzhou, 215006, China
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25
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Liu P, Xie N. RFWD2 increases proliferation and CDDP resistance of osteosarcoma cells. Gene 2025; 933:148973. [PMID: 39349111 DOI: 10.1016/j.gene.2024.148973] [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: 06/13/2024] [Revised: 09/13/2024] [Accepted: 09/26/2024] [Indexed: 10/02/2024]
Abstract
P53, a key tumor suppressor gene, usually produces mtp53 proteins with oncogenic functions due to missense mutations in the DNA-binding domain. P53 is the most commonly mutated gene in osteosarcoma and plays an important role in the development and metastasis of osteosarcoma. The ubiquitin proteasome system is an evolutionarily conserved post-translational modification that regulates a variety of disease processes, including tumors. Researches have shown that RFWD2, as a function of an E3 ubiquitin ligase, plays an important role in regulating tumor progression. However, the biological function of RFWD2 in osteosarcoma cells with different p53 status remains to be clarified. Initially, we found that sarcoma patients with high levels of RFWD2 expression tended to have shorter overall survival time by analyzing UALCAN-TCGA data. Subsequently, we used CCK-8, colony formation, Transwell, and xenograft methods to confirm that RFWD2 acts as an oncogene, regulating the proliferation and invasion of osteosarcoma cells (HOS(p53mut/-), U2OS(p53wt/wt) and Saos-2(p53-/-) cells) with different p53 status. Further co-IP experiments showed that in HOS(p53mut/-) and U2OS(p53wt/wt) cells, RFWD2 binds to p53 and participate in tumor progression. In addition, we demonstrated through both in vitro and in vivo experiments that RFWD2 regulates the sensitivity of osteosarcoma cells to CDDP. In conclusion, our study demonstrates that RFWD2 acts as an oncogene regulating osteosarcoma cell proliferation and sensitivity to CDDP. Our findings provide a new perspective and potential therapeutic target for the treatment of osteosarcoma.
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Affiliation(s)
- Pingting Liu
- Department of Health Management Center, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, China
| | - Na Xie
- Department of Pediatrics, Hunan Provincial Maternal and Child Health Care Hospital, Changsha 410008, China.
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26
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Rees A, Villamor E, Evans D, Gooz M, Fallon C, Mina-Abouda M, Disharoon A, Eblen ST, Delaney JR. Screening Methods to Discover the FDA-Approved Cancer Drug Encorafenib as Optimally Selective for Metallothionein Gene Loss Ovarian Cancer. Genes (Basel) 2025; 16:42. [PMID: 39858588 PMCID: PMC11764637 DOI: 10.3390/genes16010042] [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: 12/07/2024] [Revised: 12/26/2024] [Accepted: 12/28/2024] [Indexed: 01/27/2025] Open
Abstract
BACKGROUND/OBJECTIVES All 11 metallothionein protein-coding genes are located on human chromosome 16q13. It is unique among human genetics to have an entire pathway's genes clustered in a short chromosomal region. Since solid tumors, particularly high-grade serous ovarian cancer (HGSC), exhibit high rates of monoallelic aneuploidy, this region is commonly lost. Studies have not yet been performed to determine what vulnerability may be created in cancer cells with low metallothionein expression. Here, a screen of FDA-approved cancer small molecule drugs for those best targeting low metallothionein ovarian cancer was completed. METHODS Screening methods were tested and compared using vehicle-treated negative controls and cadmium chloride, a positive control for cell loss selective for low metallothionein cells. CAOV3 cells, which are unique in their expression of only two metallothionein isoforms, were used, with or without shRNA knockdown of the predominantly expressed MT2A gene. A library of FDA-approved molecules was then screened. RESULTS The optimal assay utilized Hoechst 33342 nuclear staining and mechanized fluorescent microscope counting of cell content. Encorafenib, an RAF inhibitor, was identified as the most selective for enhanced cytotoxicity in MT2A knockdown cells compared to scrambled controls. CONCLUSIONS The nuclear stain Hoechst 33342, assessed by fluorescence microscopy, provides a low variance, moderate throughput platform for cancer cell loss screens. Low metallothionein ovarian cancer cells exhibit a vulnerability to the RAF inhibitor encorafenib.
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Affiliation(s)
- Amy Rees
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Evan Villamor
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Della Evans
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Monika Gooz
- Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Clare Fallon
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Mirna Mina-Abouda
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Andrew Disharoon
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Scott T. Eblen
- Department of Pharmacology and Immunology, Medical University of South Carolina, Charleston, SC 29425, USA
| | - Joe R. Delaney
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC 29425, USA
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27
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Cui Z, Liu C, Li H, Wang J, Li G. Analysis and Validation of Tyrosine Metabolism-related Prognostic Features for Liver Hepatocellular Carcinoma Therapy. Curr Med Chem 2025; 32:160-187. [PMID: 38415454 DOI: 10.2174/0109298673290101240223074545] [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: 10/30/2023] [Revised: 01/19/2024] [Accepted: 02/15/2024] [Indexed: 02/29/2024]
Abstract
AIMS To explore tyrosine metabolism-related characteristics in liver hepatocellular carcinoma (LIHC) and to establish a risk signature for the prognostic prediction of LIHC. Novel prognostic signatures contribute to the mining of novel biomarkers, which are essential for the construction of a precision medicine system for LIHC and the improvement of survival. BACKGROUND Tyrosine metabolism plays a critical role in the initiation and development of LIHC. Based on the tyrosine metabolism-related characteristics in LIHC, this study developed a risk signature to improve the prognostic prediction of patients with LIHC. OBJECTIVE To investigate the correlation between tyrosine metabolism and progression of LIHC and to develop a tyrosine metabolism-related prognostic model. METHODS Gene expression and clinicopathological information of LIHC were obtained from The Cancer Genome Atlas (TCGA) database. Distinct subtypes of LIHC were classified by performing consensus cluster analysis on the tyrosine metabolism-related genes. Univariate and Lasso Cox regression were used to develop a RiskScore prognosis model. Kaplan-Meier (KM) survival analysis with log-rank test and area under the curve (AUC) of receiver operating characteristic (ROC) were employed in the prognostic evaluation and prediction validation. Immune infiltration, tyrosine metabolism score, and pathway enrichment were evaluated using single-sample gene set enrichment analysis (ssGSEA). Finally, a nomogram model was developed with the RiskScore and other clinicopathological features. RESULTS Based on the tyrosine metabolism genes in the TCGA cohort, we identified 3 tyrosine metabolism-related subtypes showing significant prognostic differences. Four candidate genes selected from the common differentially expressed genes (DEGs) between the 3 subtypes were used to develop a RiskScore model, which could effectively divide LIHC patients into high- and lowrisk groups. In both the training and validation sets, high-risk patients tended to have worse overall survival, less active immunotherapy response, higher immune infiltration and clinical grade, and higher oxidative, fatty, and xenobiotic metabolism pathways. Multivariate analysis confirmed that the RiskScore was an independent indicator for the prognosis of LIHC. The results from pan-- cancer analysis also supported that the RiskScore had a strong prognostic performance in other cancers. The nomogram demonstrated that the RiskScore contributed the most to the prediction of LIHC prognosis. CONCLUSION Our study developed a tyrosine metabolism-related risk model that performed well in survival prediction, showing the potential to serve as an independent prognostic predictor for LIHC treatment.
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Affiliation(s)
- Zhongfeng Cui
- Department of Clinical Laboratory, Henan Provincial Infectious Disease Hospital, Zhengzhou, 450000, China
| | - Chunli Liu
- Department of Infectious Diseases and Hepatology, Henan Provincial Infectious Disease Hospital, Zhengzhou, 450000, China
| | - Hongzhi Li
- Department of Tuberculosis, Henan Provincial Infectious Disease Hospital, Zhengzhou, 450000, China
| | - Juan Wang
- Department of Infectious Diseases and Hepatology, Henan Provincial Infectious Disease Hospital, Zhengzhou, 450000, China
| | - Guangming Li
- Department of Infectious Diseases and Hepatology, Henan Provincial Infectious Disease Hospital, Zhengzhou, 450000, China
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28
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Tornesello ML. TP53 mutations in cancer: Molecular features and therapeutic opportunities (Review). Int J Mol Med 2025; 55:7. [PMID: 39450536 PMCID: PMC11554381 DOI: 10.3892/ijmm.2024.5448] [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: 07/10/2024] [Accepted: 09/03/2024] [Indexed: 10/26/2024] Open
Abstract
The tumour suppressor factor p53 plays an essential role in regulating numerous cellular processes, including the cell cycle, DNA repair, apoptosis, autophagy, cell metabolism and immune response. TP53 is the most commonly mutated gene in human cancers. These mutations are primarily non‑synonymous changes that produce mutant p53 proteins characterized by loss of function, a dominant negative effect on p53 tetramerisation and gain of function (GOF). GOF mutations not only disrupt the tumour‑suppressive activities of p53 but also endow the mutant proteins with new oncogenic properties. Recent studies analysing different pathogenic features of mutant p53 in cancer‑derived cell lines have demonstrated that restoring wild‑type p53, rather than removing GOF mutations, reduces cancer cell growth. These findings suggest that therapeutic strategies for reactivating wild‑type p53 function in cancer cells may bring a greater benefit than approaches halting mutant p53. This approach could involve the use of small molecules, gene therapy and other methods to re‑establish wild‑type p53 activity. This review describes the complexity of the biological activities of different p53 mutants and summarizes the current therapeutic approaches to restore p53 function.
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Affiliation(s)
- Maria Lina Tornesello
- Molecular Biology and Viral Oncology Unit, Istituto Nazionale Tumori IRCCS Fondazione G. Pascale, I-80131 Napoli, Italy
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29
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Funk JS, Klimovich M, Drangenstein D, Pielhoop O, Hunold P, Borowek A, Noeparast M, Pavlakis E, Neumann M, Balourdas DI, Kochhan K, Merle N, Bullwinkel I, Wanzel M, Elmshäuser S, Teply-Szymanski J, Nist A, Procida T, Bartkuhn M, Humpert K, Mernberger M, Savai R, Soussi T, Joerger AC, Stiewe T. Deep CRISPR mutagenesis characterizes the functional diversity of TP53 mutations. Nat Genet 2025; 57:140-153. [PMID: 39774325 PMCID: PMC11735402 DOI: 10.1038/s41588-024-02039-4] [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: 03/17/2024] [Accepted: 11/20/2024] [Indexed: 01/11/2025]
Abstract
The mutational landscape of TP53, a tumor suppressor mutated in about half of all cancers, includes over 2,000 known missense mutations. To fully leverage TP53 mutation status for personalized medicine, a thorough understanding of the functional diversity of these mutations is essential. We conducted a deep mutational scan using saturation genome editing with CRISPR-mediated homology-directed repair to engineer 9,225 TP53 variants in cancer cells. This high-resolution approach, covering 94.5% of all cancer-associated TP53 missense mutations, precisely mapped the impact of individual mutations on tumor cell fitness, surpassing previous deep mutational scan studies in distinguishing benign from pathogenic variants. Our results revealed even subtle loss-of-function phenotypes and identified promising mutants for pharmacological reactivation. Moreover, we uncovered the roles of splicing alterations and nonsense-mediated messenger RNA decay in mutation-driven TP53 dysfunction. These findings underscore the power of saturation genome editing in advancing clinical TP53 variant interpretation for genetic counseling and personalized cancer therapy.
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Affiliation(s)
- Julianne S Funk
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | - Maria Klimovich
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | | | - Ole Pielhoop
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | - Pascal Hunold
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | - Anna Borowek
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | - Maxim Noeparast
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | | | - Michelle Neumann
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | - Dimitrios-Ilias Balourdas
- Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt am Main, Germany
- Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Frankfurt am Main, Germany
| | - Katharina Kochhan
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | - Nastasja Merle
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | - Imke Bullwinkel
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | - Michael Wanzel
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | | | - Julia Teply-Szymanski
- Institute of Pathology, Philipps-University, Marburg University Hospital, Marburg, Germany
| | - Andrea Nist
- Genomics Core Facility, Philipps-University, Marburg, Germany
| | - Tara Procida
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
| | - Marek Bartkuhn
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
- Biomedical Informatics and Systems Medicine, Justus-Liebig-University, Giessen, Germany
| | - Katharina Humpert
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
- Bioinformatics Core Facility, Philipps-University, Marburg, Germany
| | - Marco Mernberger
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany
| | - Rajkumar Savai
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany
- Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany
- Cardio-Pulmonary Institute (CPI), Giessen, Germany
- Lung Microenvironmental Niche in Cancerogenesis, Max Planck Institute for Heart and Lung Research, Bad Nauheim, Germany
| | - Thierry Soussi
- Centre de Recherche Saint-Antoine UMRS_938, INSERM, Sorbonne Université, Paris, France
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Clinical Genetics, Uppsala University Hospital, Uppsala, Sweden
| | - Andreas C Joerger
- Institute of Pharmaceutical Chemistry, Goethe University, Frankfurt am Main, Germany
- Buchmann Institute for Molecular Life Sciences and Structural Genomics Consortium (SGC), Frankfurt am Main, Germany
| | - Thorsten Stiewe
- Institute of Molecular Oncology, Philipps-University, Marburg, Germany.
- Genomics Core Facility, Philipps-University, Marburg, Germany.
- Institute for Lung Health (ILH), Justus Liebig University, Giessen, Germany.
- Bioinformatics Core Facility, Philipps-University, Marburg, Germany.
- Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Giessen, Germany.
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30
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Janic A, Abad E, Amelio I. Decoding p53 tumor suppression: a crosstalk between genomic stability and epigenetic control? Cell Death Differ 2025; 32:1-8. [PMID: 38379088 PMCID: PMC11742645 DOI: 10.1038/s41418-024-01259-9] [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: 10/03/2023] [Revised: 01/22/2024] [Accepted: 01/23/2024] [Indexed: 02/22/2024] Open
Abstract
Genomic instability, a hallmark of cancer, is a direct consequence of the inactivation of the tumor suppressor protein p53. Genetically modified mouse models and human tumor samples have revealed that p53 loss results in extensive chromosomal abnormalities, from copy number alterations to structural rearrangements. In this perspective article we explore the multifaceted relationship between p53, genomic stability, and epigenetic control, highlighting its significance in cancer biology. p53 emerges as a critical regulator of DNA repair mechanisms, influencing key components of repair pathways and directly participating in DNA repair processes. p53 role in genomic integrity however extends beyond its canonical functions. p53 influences also epigenetic landscape, where it modulates DNA methylation and histone modifications. This epigenetic control impacts the expression of genes involved in tumor suppression and oncogenesis. Notably, p53 ability to ensure cellular response to DNA demethylation contributes to the maintenance of genomic stability by preventing unscheduled transcription of repetitive non-coding genomic regions. This latter indicates a causative relationship between the control of epigenetic stability and the maintenance of genomic integrity in p53-mediated tumor suppression. Understanding these mechanisms offers promising avenues for innovative therapeutic strategies targeting epigenetic dysregulation in cancer and emphasizes the need for further research to unravel the complexities of this relationship. Ultimately, these insights hold the potential to transform cancer treatment and prevention strategies.
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Affiliation(s)
- Ana Janic
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain.
| | - Etna Abad
- Department of Medicine and Life Sciences, Universitat Pompeu Fabra, Barcelona, Spain
| | - Ivano Amelio
- Chair for Systems Toxicology, University of Konstanz, Konstanz, Germany.
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31
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Pavlova S, Malcikova J, Radova L, Bonfiglio S, Cowland JB, Brieghel C, Andersen MK, Karypidou M, Biderman B, Doubek M, Lazarian G, Rapado I, Vynck M, Porret NA, Andres M, Rosenberg D, Sahar D, Martínez‐Laperche C, Buño I, Hindley A, Donaldson D, Sánchez JB, García‐Marco JA, Serrano‐Alcalá A, Ferrer‐Lores B, Fernández‐Rodriguez C, Bellosillo B, Stilgenbauer S, Tausch E, Nikdin H, Quinn F, Atkinson E, van de Corput L, Yildiz C, Bilbao‐Sieyro C, Florido Y, Thiede C, Schuster C, Stoj A, Czekalska S, Chatzidimitriou A, Laidou S, Bidet A, Dussiau C, Nollet F, Piras G, Monne M, Smirnova S, Nikitin E, Sloma I, Claudel A, Largeaud L, Ysebaert L, Valk PJM, Christian A, Walewska R, Oscier D, Sebastião M, da Silva MG, Galieni P, Angelini M, Rossi D, Spina V, Matos S, Martins V, Stokłosa T, Pepek M, Baliakas P, Andreu R, Luna I, Kahre T, Murumets Ü, Pikousova T, Kurucova T, Laird S, Ward D, Alcoceba M, Balanzategui A, Scarfo L, Gandini F, Zapparoli E, Blanco A, Abrisqueta P, Rodríguez‐Vicente AE, Benito R, Bravetti C, Davi F, Gameiro P, Martinez‐Lopez J, Tazón‐Vega B, Baran‐Marszak F, Davis Z, Catherwood M, Sudarikov A, Rosenquist R, Niemann CU, Stamatopoulos K, Ghia P, Pospisilova S. Detection of clinically relevant variants in the TP53 gene below 10% allelic frequency: A multicenter study by ERIC, the European Research Initiative on CLL. Hemasphere 2025; 9:e70065. [PMID: 39840379 PMCID: PMC11746920 DOI: 10.1002/hem3.70065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2024] [Revised: 10/04/2024] [Accepted: 11/13/2024] [Indexed: 01/23/2025] Open
Abstract
In chronic lymphocytic leukemia, the reliability of next-generation sequencing (NGS) to detect TP53 variants ≤10% allelic frequency (low-VAF) is debated. We tested the ability to detect 23 such variants in 41 different laboratories using their NGS method of choice. The sensitivity was 85.6%, 94.5%, and 94.8% at 1%, 2%, and 3% VAF cut-off, respectively. While only one false positive (FP) result was reported at >2% VAF, it was more challenging to distinguish true variants <2% VAF from background noise (37 FPs reported by 9 laboratories). The impact of low-VAF variants on time-to-second-treatment (TTST) and overall survival (OS) was investigated in a series of 1092 patients. Among patients not treated with targeted agents, patients with low-VAF TP53 variants had shorter TTST and OS versus wt-TP53 patients, and the relative risk of second-line treatment or death increased continuously with increasing VAF. Targeted therapy in ≥2 line diminished the difference in OS between patients with low-VAF TP53 variants and wt-TP53 patients, while patients with high-VAF TP53 variants had inferior OS compared to wild type-TP53 cases. Altogether, NGS-based approaches are technically capable of detecting low-VAF variants. No strict threshold can be suggested from a technical standpoint, laboratories reporting TP53 mutations should participate in a standardized validation set-up. Finally, whereas low-VAF variants affected outcomes in patients receiving chemoimmunotherapy, their impact on those treated with novel therapies remains undetermined. Our results pave the way for the harmonized and accurate TP53 assessment, which is indispensable for elucidating the role of TP53 mutations in targeted treatment.
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Affiliation(s)
- Sarka Pavlova
- Department of Internal Medicine, Hematology and Oncology, and Institute of Medical Genetics and Genomics, University Hospital Brno and Medical FacultyMasaryk UniversityBrnoCzech Republic
- Centre for Molecular Medicine, Central European Institute of Technology (CEITEC)Masaryk UniversityBrnoCzech Republic
| | - Jitka Malcikova
- Department of Internal Medicine, Hematology and Oncology, and Institute of Medical Genetics and Genomics, University Hospital Brno and Medical FacultyMasaryk UniversityBrnoCzech Republic
- Centre for Molecular Medicine, Central European Institute of Technology (CEITEC)Masaryk UniversityBrnoCzech Republic
| | - Lenka Radova
- Centre for Molecular Medicine, Central European Institute of Technology (CEITEC)Masaryk UniversityBrnoCzech Republic
| | - Silvia Bonfiglio
- B‐Cell Neoplasia Unit and Strategic Research Program on CLLIRCCS Ospedale San RaffaeleMilanItaly
- Center for Omics SciencesIRCCS Ospedale San RaffaeleMilanItaly
| | - Jack B. Cowland
- Department of Clinical Genetics, Centre of Diagnostic InvestigationsCopenhagen University Hospital ‐ RigshospitaletCopenhagenDenmark
| | - Christian Brieghel
- Department of HematologyCopenhagen University Hospital ‐ RigshospitaletCopenhagenDenmark
| | - Mette K. Andersen
- Department of Clinical Genetics, Centre of Diagnostic InvestigationsCopenhagen University Hospital ‐ RigshospitaletCopenhagenDenmark
| | - Maria Karypidou
- Institute of Applied BiosciencesCentre for Research and Technology HellasThessalonikiGreece
| | - Bella Biderman
- National Medical Research Center for HematologyMoscowRussia
| | - Michael Doubek
- Department of Internal Medicine, Hematology and Oncology, and Institute of Medical Genetics and Genomics, University Hospital Brno and Medical FacultyMasaryk UniversityBrnoCzech Republic
- Centre for Molecular Medicine, Central European Institute of Technology (CEITEC)Masaryk UniversityBrnoCzech Republic
| | - Gregory Lazarian
- Hematology laboratoryHUPSSD, Hôpital Avicenne, APHPBobignyFrance
- INSERM U978Université Sorbonne Paris NordBobignyFrance
| | - Inmaculada Rapado
- Department of HematologyHospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Complutense University, CNIO, CIBERONCMadridSpain
| | - Matthijs Vynck
- Department of Laboratory MedicineAZ Sint‐Jan HospitalBrugesBelgium
| | - Naomi A. Porret
- Department of Hematology and Central Hematology Laboratory, InselspitalBern University Hospital, University of BernBernSwitzerland
| | - Martin Andres
- Department of Hematology and Central Hematology Laboratory, InselspitalBern University Hospital, University of BernBernSwitzerland
| | | | - Dvora Sahar
- Hematology LaboratoryRambam Medical CenterHaifaIsrael
| | - Carolina Martínez‐Laperche
- Department of HematologyGregorio Marañón General University Hospital, Gregorio Marañón Health Research Institute (IiSGM)MadridSpain
| | - Ismael Buño
- Department of HematologyGregorio Marañón General University Hospital, Gregorio Marañón Health Research Institute (IiSGM)MadridSpain
- Genomics UnitGregorio Marañón General University Hospital, Gregorio Marañón Health Research Institute (IiSGM)MadridSpain
- Department of Cell Biology, Medical SchoolComplutense University of MadridMadridSpain
| | | | | | - Julio B. Sánchez
- Molecular Cytogenetics Unit, Hematology DepartmentHospital Universitario Puerta de Hierro‐MajadahondaMadridSpain
| | - José A. García‐Marco
- Molecular Cytogenetics Unit, Hematology DepartmentHospital Universitario Puerta de Hierro‐MajadahondaMadridSpain
| | | | | | | | - Beatriz Bellosillo
- Pathology DepartmentHospital del Mar, IMIM (Hospital del Mar Medical Research Institute)BarcelonaSpain
| | | | - Eugen Tausch
- Department of Internal Medicine IIIUlm UniversityUlmGermany
| | - Hero Nikdin
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
- Department of Clinical Genetics and GenomicsKarolinska University HospitalStockholmSweden
| | - Fiona Quinn
- Cancer Molecular Diagnostics DepartmentCentre for Laboratory Medicine and Molecular Pathology, St. James HospitalDublinIreland
| | - Emer Atkinson
- Cancer Molecular Diagnostics DepartmentCentre for Laboratory Medicine and Molecular Pathology, St. James HospitalDublinIreland
| | - Lisette van de Corput
- Central Diagnostic LaboratoryUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Cafer Yildiz
- Central Diagnostic LaboratoryUniversity Medical Center UtrechtUtrechtThe Netherlands
| | - Cristina Bilbao‐Sieyro
- Servicio de HematologíaHospital Universitario de Gran Canaria Dr. Negrín, Departamento de Morfología de La Universidad de Las Palmas de Gran CanariaGran CanariaSpain
| | - Yanira Florido
- Servicio de HematologíaHospital Universitario de Gran Canaria Dr. Negrín, Departamento de Morfología de La Universidad de Las Palmas de Gran CanariaGran CanariaSpain
| | | | | | - Anastazja Stoj
- Department of Hematological Diagnostics and GeneticsUniversity Hospital in KrakowKrakowPoland
| | - Sylwia Czekalska
- Department of Hematological Diagnostics and GeneticsUniversity Hospital in KrakowKrakowPoland
| | | | - Stamatia Laidou
- Institute of Applied BiosciencesCentre for Research and Technology HellasThessalonikiGreece
| | - Audrey Bidet
- Laboratoire d'Hématologie BiologiqueCHU BordeauxBordeauxFrance
| | - Charles Dussiau
- Laboratoire d'Hématologie BiologiqueCHU BordeauxBordeauxFrance
| | - Friedel Nollet
- Department of Laboratory MedicineAZ Sint‐Jan HospitalBrugesBelgium
| | - Giovanna Piras
- Laboratorio specialistico UOC ematologiaOspedale San FrancescoASL NuoroItaly
| | - Maria Monne
- Laboratorio specialistico UOC ematologiaOspedale San FrancescoASL NuoroItaly
| | | | - Eugene Nikitin
- Outpatient department of Hematology, Oncology and Chemotherapy, Botkin Hospital, and Department of Hematology and TransfusiologyRussian Medical Academy of Continuous Professional EducationMoscowRussia
| | - Ivan Sloma
- Univ Paris Est Creteil, INSERM, IMRBCreteilFrance
- Departement d'Hematologie et Immunologie BiologiqueAP‐HP, Hopital Henri MondorCreteilFrance
| | - Alexis Claudel
- Univ Paris Est Creteil, INSERM, IMRBCreteilFrance
- Departement d'Hematologie et Immunologie BiologiqueAP‐HP, Hopital Henri MondorCreteilFrance
| | | | - Loïc Ysebaert
- Institut Universitaire de Cancérologie de ToulouseToulouseFrance
| | - Peter J. M. Valk
- Department of Hematology, Erasmus MC Cancer InstituteUniversity Medical Center RotterdamRotterdamThe Netherlands
| | - Amy Christian
- Molecular PathologyUniversity Hospitals DorsetBournemouthUK
| | | | - David Oscier
- Molecular PathologyUniversity Hospitals DorsetBournemouthUK
| | - Marta Sebastião
- Laboratório Hemato‐OncologiaInstituto Português de Oncologia de LisboaLisbonPortugal
| | | | - Piero Galieni
- UOC HematologyMazzoni Hospital‐Ascoli PicenoAscoli PicenoItaly
| | - Mario Angelini
- UOC HematologyMazzoni Hospital‐Ascoli PicenoAscoli PicenoItaly
| | - Davide Rossi
- Institute of Oncology Research and OncologyInstitute of Southern SwitzerlandBellinzonaSwitzerland
| | - Valeria Spina
- Laboratorio di Diagnostica Molecolare, Servizio di Genetica Medica EOLABEnte Ospedaliero CantonaleBellinzonaSwitzerland
| | - Sónia Matos
- Genomed‐Diagnósticos de Medicina MoleculariMM ‐ Instituto de Medicina Molecular, Faculdade de MedicinaLisboaPortugal
| | - Vânia Martins
- Genomed‐Diagnósticos de Medicina MoleculariMM ‐ Instituto de Medicina Molecular, Faculdade de MedicinaLisboaPortugal
| | - Tomasz Stokłosa
- Department of Tumor Biology and GeneticsMedical University of WarsawWarsawPoland
| | - Monika Pepek
- Department of Tumor Biology and GeneticsMedical University of WarsawWarsawPoland
| | - Panagiotis Baliakas
- Department of Immunology, Genetics and PathologyUppsala UniversityUppsalaSweden
| | - Rafa Andreu
- Hematology DepartmentHospital Universitari i Politècnic la FeValenciaSpain
| | - Irene Luna
- Hematology DepartmentHospital Universitari i Politècnic la FeValenciaSpain
| | - Tiina Kahre
- Department of Laboratory Genetics, Genetics and Personalized ClinicTartu University HospitalTartuEstonia
- Genetics and Personalized Medicine Clinic, Institute of Clinical MedicineTartu UniversityTartuEstonia
| | - Ülle Murumets
- Department of Laboratory Genetics, Genetics and Personalized ClinicTartu University HospitalTartuEstonia
| | - Tereza Pikousova
- Centre for Molecular Medicine, Central European Institute of Technology (CEITEC)Masaryk UniversityBrnoCzech Republic
| | - Terezia Kurucova
- Centre for Molecular Medicine, Central European Institute of Technology (CEITEC)Masaryk UniversityBrnoCzech Republic
| | - Sophie Laird
- Wessex Genomics Laboratory ServiceSalisbury NHS Foundation TrustSalisburyUK
| | - Daniel Ward
- Wessex Genomics Laboratory ServiceSalisbury NHS Foundation TrustSalisburyUK
| | - Miguel Alcoceba
- Department of HematologyUniversity Hospital of Salamanca (HUS/IBSAL), CIBERONC and Cancer Research Center of Salamanca‐IBMCC (USAL‐CSIC)SalamancaSpain
| | - Ana Balanzategui
- Department of HematologyUniversity Hospital of Salamanca (HUS/IBSAL), CIBERONC and Cancer Research Center of Salamanca‐IBMCC (USAL‐CSIC)SalamancaSpain
| | - Lydia Scarfo
- B‐Cell Neoplasia Unit and Strategic Research Program on CLLIRCCS Ospedale San RaffaeleMilanItaly
- Medical SchoolUniversità Vita‐Salute San RaffaeleMilanItaly
| | - Francesca Gandini
- B‐Cell Neoplasia Unit and Strategic Research Program on CLLIRCCS Ospedale San RaffaeleMilanItaly
- Medical SchoolUniversità Vita‐Salute San RaffaeleMilanItaly
| | | | - Adoración Blanco
- Department of HematologyHospital Universitari Vall d'Hebron (HUVH)BarcelonaSpain
- Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO)BarcelonaSpain
- Department of MedicineUniversitat Autònoma de Barcelona (UAB)BarcelonaSpain
| | - Pau Abrisqueta
- Department of HematologyHospital Universitari Vall d'Hebron (HUVH)BarcelonaSpain
- Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO)BarcelonaSpain
- Department of MedicineUniversitat Autònoma de Barcelona (UAB)BarcelonaSpain
| | - Ana E. Rodríguez‐Vicente
- Oncohematology Research Group, Institute of Biomedical Research of Salamanca (IBSAL)Cancer Research Centre (IBMCC, USAL‐CSIC) and University of SalamancaSalamancaSpain
- Department of Human Anatomy and Histology, Faculty of MedicineUniversity of SalamancaSalamancaSpain
| | - Rocío Benito
- Oncohematology Research Group, Institute of Biomedical Research of Salamanca (IBSAL)Cancer Research Centre (IBMCC, USAL‐CSIC) and University of SalamancaSalamancaSpain
| | - Clotilde Bravetti
- Department of Biological HematologySorbonne Université, AP‐HP, Pitié‐Salpêtrière HospitalParisFrance
| | - Frédéric Davi
- Department of Biological HematologySorbonne Université, AP‐HP, Pitié‐Salpêtrière HospitalParisFrance
| | - Paula Gameiro
- Laboratório Hemato‐OncologiaInstituto Português de Oncologia de LisboaLisbonPortugal
| | - Joaquin Martinez‐Lopez
- Department of HematologyHospital Universitario 12 de Octubre, Instituto de Investigación Sanitaria Hospital 12 de Octubre (imas12), Complutense University, CNIO, CIBERONCMadridSpain
| | - Bárbara Tazón‐Vega
- Department of HematologyHospital Universitari Vall d'Hebron (HUVH)BarcelonaSpain
- Experimental Hematology, Vall d'Hebron Institute of Oncology (VHIO)BarcelonaSpain
- Department of MedicineUniversitat Autònoma de Barcelona (UAB)BarcelonaSpain
| | - Fanny Baran‐Marszak
- Hematology laboratoryHUPSSD, Hôpital Avicenne, APHPBobignyFrance
- INSERM U978Université Sorbonne Paris NordBobignyFrance
| | - Zadie Davis
- Molecular PathologyUniversity Hospitals DorsetBournemouthUK
| | | | | | - Richard Rosenquist
- Department of Molecular Medicine and SurgeryKarolinska InstitutetStockholmSweden
- Department of Clinical Genetics and GenomicsKarolinska University HospitalStockholmSweden
| | - Carsten U. Niemann
- Department of HematologyCopenhagen University Hospital ‐ RigshospitaletCopenhagenDenmark
| | - Kostas Stamatopoulos
- Institute of Applied BiosciencesCentre for Research and Technology HellasThessalonikiGreece
| | - Paolo Ghia
- B‐Cell Neoplasia Unit and Strategic Research Program on CLLIRCCS Ospedale San RaffaeleMilanItaly
- Medical SchoolUniversità Vita‐Salute San RaffaeleMilanItaly
| | - Sarka Pospisilova
- Department of Internal Medicine, Hematology and Oncology, and Institute of Medical Genetics and Genomics, University Hospital Brno and Medical FacultyMasaryk UniversityBrnoCzech Republic
- Centre for Molecular Medicine, Central European Institute of Technology (CEITEC)Masaryk UniversityBrnoCzech Republic
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Chui MH, Song Q, Zhu J, Jiao Y, Wang B, Wang Y, Wang TL, Vang R, Shih IM. Early Genetic Divergence of High-Grade Carcinomas Originating from Low-Grade Serous Ovarian Neoplasms. Mod Pathol 2025; 38:100629. [PMID: 39389422 DOI: 10.1016/j.modpat.2024.100629] [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: 04/28/2024] [Revised: 09/06/2024] [Accepted: 09/27/2024] [Indexed: 10/12/2024]
Abstract
The current paradigm implicates a fallopian tube precursor as the origin of most ovarian high-grade serous carcinomas (HGSCs). However, a rare subset of HGSCs develop via a distinct pathway from low-grade serous ovarian neoplasms (namely, serous borderline tumors and low-grade serous carcinoma). This alternate pathway for the development of HGSC and other poorly differentiated carcinomas of the ovary is not well understood. To elucidate the molecular pathogenesis and evolutionary trajectory of histologic transformation of low-grade serous neoplasms, we performed whole exome sequencing on microdissected low-grade and higher-grade components from 7 cases of serous borderline tumor or low-grade serous carcinoma associated with a synchronous or metachronous indeterminate/high-grade carcinoma. In most cases, there were relatively few somatic mutations shared between matched low-grade and higher-grade tumors compared with private mutations specific to each component (ie, phylogenetic trees with short trunks and long branches). Truncal mutations, present across all tumor samples from a given patient, included known drivers of low-grade serous neoplasms: KRAS (G12D, n = 4), BRAF (G469A, n = 1), NF2 (n = 1), and USP9X (n = 1). Transformation to HGSC was associated with a TP53 mutation with bi-allelic inactivation in 3 cases, all with severe nuclear atypia, and associated with genome-wide copy number alterations and allelic imbalances. TP53-wildtype tumors comprised a morphologic spectrum, which included indeterminate-grade serous carcinomas with moderate nuclear atypia and high mitotic activity, although lacking extensive chromosomal instability (n = 2) and poorly differentiated carcinomas (n = 2, including a high-grade Mullerian carcinoma and an undifferentiated carcinoma with sarcomatoid features). In summary, synchronous and metachronous low-grade serous neoplasms and higher-grade carcinomas are clonally related. Early genetic divergence, most evident in cases with TP53 mutations, suggests that high-grade transformation may be a relatively early molecular event.
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Affiliation(s)
- M Herman Chui
- Department of Pathology and Laboratory Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
| | - Qianqian Song
- State Key Lab of Molecular Oncology, Laboratory of Cell and Molecular Biology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Jiarun Zhu
- State Key Lab of Molecular Oncology, Laboratory of Cell and Molecular Biology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Yuchen Jiao
- State Key Lab of Molecular Oncology, Laboratory of Cell and Molecular Biology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China
| | - Brant Wang
- Department of Pathology, Inova Fairfax Hospital, Falls Church, Virginia
| | - Yeh Wang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Tian-Li Wang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Russell Vang
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Gynecology/Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland
| | - Ie-Ming Shih
- Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, Maryland; Department of Gynecology/Obstetrics, Johns Hopkins Medical Institutions, Baltimore, Maryland
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Casanova J, Babiciu A, Duarte GS, da Costa AG, Serra SS, Costa T, Catarino A, Leitão MM, Lima J. Abnormal p53 High-Grade Endometrioid Endometrial Cancer: A Systematic Review and Meta-Analysis. Cancers (Basel) 2024; 17:38. [PMID: 39796669 PMCID: PMC11718986 DOI: 10.3390/cancers17010038] [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: 10/31/2024] [Revised: 12/22/2024] [Accepted: 12/23/2024] [Indexed: 01/13/2025] Open
Abstract
OBJECTIVE Our primary objective was to evaluate the oncologic outcomes of patients with abnormal p53 FIGO grade 3 (high-grade) endometrioid endometrial cancer. As secondary objectives, we determined the global prevalence of abnormal p53 in grade 3 endometrioid endometrial carcinomas and the geographical variations. METHODS The following electronic databases were searched: PubMed/Medline, EMBASE, Cochrane Library, Scopus, and Web of Science. We followed the Meta-Analysis for Observational Studies in Epidemiology guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses. This review was preregistered with PROSPERO (no: CRD42023495192). Bias was assessed using the Quality in Prognosis Studies tool. For time-to-event data, the effect of p53 status on grade 3 endometrial cancer was described using hazard ratios (HRs) and corresponding 95% confidence intervals (CIs). Overall survival and progression-free survival were analyzed using one- and two-stage approaches, the Kaplan-Meier method, and Cox proportional hazards models. RESULTS Fifty-seven studies with 2528 patients were included. Patients with abnormal p53 had an increased risk of death (HR, 1.29 (95% CI, 1.11-1.48); I2 = 88%) and disease progression (HR, 1.63; 95% CI, 1.42-1.88; I2 = 2%) compared with patients with wildtype p53 G3 endometrial cancer. The global pooled prevalence of abnormal p53 was 30% (95% CI, 25-34%; tau2 = 0.02; I2 = 74%), with the highest prevalence being found in studies conducted in Asia (95% CI, 27-41%; tau2 = 0.01; I2 = 52%). CONCLUSIONS Abnormal p53 grade 3 endometrioid endometrial cancer is more common in Asia, and it is associated with decreased overall survival and progression-free survival.
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Affiliation(s)
- João Casanova
- Gynecologic Oncology Unit, Obstetrics and Gynecology Service, Department of Surgery, Hospital da Luz Lisboa, 1500-650 Lisbon, Portugal; (J.C.); (A.G.d.C.)
| | - Alexandru Babiciu
- Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, 1649-004 Lisbon, Portugal; (A.B.); (G.S.D.)
| | - Gonçalo S. Duarte
- Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, 1649-004 Lisbon, Portugal; (A.B.); (G.S.D.)
- Clinical Pharmacology Unit, Unidade Local de Saúde Santa Maria, 1649-035 Lisbon, Portugal
| | - Ana Gomes da Costa
- Gynecologic Oncology Unit, Obstetrics and Gynecology Service, Department of Surgery, Hospital da Luz Lisboa, 1500-650 Lisbon, Portugal; (J.C.); (A.G.d.C.)
| | - Sofia Silvério Serra
- Library of NOVA Medical School, Universidade Nova de Lisboa, 1099-085 Lisbon, Portugal; (S.S.S.); (T.C.)
| | - Teresa Costa
- Library of NOVA Medical School, Universidade Nova de Lisboa, 1099-085 Lisbon, Portugal; (S.S.S.); (T.C.)
| | - Ana Catarino
- Department of Pathology, Hospital da Luz Lisboa, 1500-650 Lisbon, Portugal;
| | - Mário M. Leitão
- Gynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA;
- Gynecologic Service, Weil Cornell Medical College, New York, NY 10065, USA
| | - Jorge Lima
- Comprehensive Health Research Center (CHRC), NOVA Medical School, Faculdade de Ciências Médicas, NMS, FCM, Universidade NOVA de Lisboa, 1099-085 Lisbon, Portugal
- Department of Obstetrics and Gynecology, Luz Saúde, Hospital da Luz Lisboa, 1500-650 Lisbon, Portugal
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Bronowicka-Szydełko A, Rabczyński M, Dumas I, Fiodorenko-Dumas Ż, Wojtczak B, Kotyra Ł, Kustrzeba-Wójcicka I, Lewandowski Ł, Ponikowska B, Kuzan A, Kluz J, Gamian A, Madziarska K. State of Knowledge About Thyroid Cancers in the Era of COVID-19-A Narrative Review. Biomedicines 2024; 12:2829. [PMID: 39767735 PMCID: PMC11672969 DOI: 10.3390/biomedicines12122829] [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: 10/26/2024] [Revised: 11/27/2024] [Accepted: 12/06/2024] [Indexed: 01/03/2025] Open
Abstract
Thyroid cancer (TC), due to its heterogeneous nature, remains a clinical challenge. Many factors can initiate the carcinogenesis process of various types of TC, which complicates diagnosis and treatment. The presented review gathers current information on specific types of TC, taking into account the effects of the COVID-19 pandemic. It is likely that COVID-19 has influenced and continues to influence the function of the thyroid gland. A high percentage of patients with COVID-19 showing simultaneous pathological changes in the thyroid suggests that SARS-CoV-2 may disrupt the function of this gland and initiate pro-oxidative mechanisms, inflammatory states, and autoimmune diseases, thereby promoting the formation of neoplastic changes. Furthermore, changes in the expression of the ACE2, TMPRSS2, CLEC4M and DPP4 genes, observed in TC, also occur in COVID-19. Therefore, it is probable that the interaction of SARS-CoV-2 with thyroid cell receptors may initiate carcinogenesis in this gland. Additionally, some drugs used in TC therapy (e.g., levothyroxine) may increase the affinity of SARS-CoV-2 for cells, which could contribute to a more severe course of COVID-19 and the emergence of long-term symptoms (post-COVID-19). Moreover, the consequences of sanitary restrictions (limited access to medical services, reduction in endocrinological and oncological procedures) that took place in many countries during the COVID-19 pandemic may lead in the future to an increased number of missed diagnoses and the emergence of aggressive cancers.
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Affiliation(s)
- Agnieszka Bronowicka-Szydełko
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.B.-S.); (Ł.K.); (I.K.-W.); (Ł.L.)
| | - Maciej Rabczyński
- Clinical Department of Diabetology, Hypertension and Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland; (M.R.); (J.K.); (K.M.)
| | - Ilias Dumas
- Department of Clinical Physiotherapy and Rehabilitation, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Żanna Fiodorenko-Dumas
- Department of Clinical Physiotherapy and Rehabilitation, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Beata Wojtczak
- University Center for General and Oncological Surgery, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Łukasz Kotyra
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.B.-S.); (Ł.K.); (I.K.-W.); (Ł.L.)
| | - Irena Kustrzeba-Wójcicka
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.B.-S.); (Ł.K.); (I.K.-W.); (Ł.L.)
| | - Łukasz Lewandowski
- Department of Medical Biochemistry, Wroclaw Medical University, 50-368 Wroclaw, Poland; (A.B.-S.); (Ł.K.); (I.K.-W.); (Ł.L.)
| | - Beata Ponikowska
- Department of Physiology and Pathophysiology, Division of Physiology, Wroclaw Medical University, 50-368 Wroclaw, Poland;
| | - Aleksandra Kuzan
- Department of Preclinical Sciences, Pharmacology and Medical Diagnostics, Wroclaw University of Science and Technology, 51-377 Wroclaw, Poland;
| | - Joanna Kluz
- Clinical Department of Diabetology, Hypertension and Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland; (M.R.); (J.K.); (K.M.)
| | - Andrzej Gamian
- Hirszfeld Institute of Immunology and Experimantal Therapy, Polish Academy of Sciences, 53-114 Wroclaw, Poland;
| | - Katarzyna Madziarska
- Clinical Department of Diabetology, Hypertension and Internal Diseases, Wroclaw Medical University, 50-556 Wroclaw, Poland; (M.R.); (J.K.); (K.M.)
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Li Q, Zhang Y, Luo S, Zhang Z, Oberg AL, Kozono DE, Lu H, Sarkaria JN, Ma L, Wang L. Identify Non-mutational p53 Functional Deficiency in Human Cancers. GENOMICS, PROTEOMICS & BIOINFORMATICS 2024; 22:qzae064. [PMID: 39325855 PMCID: PMC11702981 DOI: 10.1093/gpbjnl/qzae064] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 07/23/2024] [Accepted: 08/21/2024] [Indexed: 09/28/2024]
Abstract
An accurate assessment of p53's functional statuses is critical for cancer genomic medicine. However, there is a significant challenge in identifying tumors with non-mutational p53 inactivation which is not detectable through DNA sequencing. These undetected cases are often misclassified as p53-normal, leading to inaccurate prognosis and downstream association analyses. To address this issue, we built the support vector machine (SVM) models to systematically reassess p53's functional statuses in TP53 wild-type (TP53WT) tumors from multiple The Cancer Genome Atlas (TCGA) cohorts. Cross-validation demonstrated the good performance of the SVM models with a mean area under the receiver operating characteristic curve (AUROC) of 0.9822, precision of 0.9747, and recall of 0.9784. Our study revealed that a significant proportion (87%-99%) of TP53WT tumors actually had compromised p53 function. Additional analyses uncovered that these genetically intact but functionally impaired (termed as predictively reduced function of p53 or TP53WT-pRF) tumors exhibited genomic and pathophysiologic features akin to TP53-mutant tumors: heightened genomic instability and elevated levels of hypoxia. Clinically, patients with TP53WT-pRF tumors experienced significantly shortened overall survival or progression-free survival compared to those with predictively normal function of p53 (TP53WT-pN) tumors, and these patients also displayed increased sensitivity to platinum-based chemotherapy and radiation therapy.
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Affiliation(s)
- Qianpeng Li
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yang Zhang
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Sicheng Luo
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zhang Zhang
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Ann L Oberg
- Division of Computational Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - David E Kozono
- Department of Radiation Oncology, Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Boston, MA 02215, USA
| | - Hua Lu
- Department of Biochemistry & Molecular Biology and Tulane Cancer Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
| | - Jann N Sarkaria
- Department of Radiation Oncology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
| | - Lina Ma
- National Genomics Data Center, China National Center for Bioinformation, Beijing 100101, China
- Beijing Institute of Genomics, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Liguo Wang
- Division of Computational Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
- Department of Biochemistry and Molecular Biology, Mayo Clinic College of Medicine and Science, Rochester, MN 55905, USA
- Bioinformatics and Computational Biology Graduate Program, University of Minnesota Rochester, Rochester, MN 55904, USA
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Skuli S, Matthews A, Carroll M, Lai C. A line in shifting sand: Can we define and target TP53 mutated MDS? Semin Hematol 2024; 61:449-456. [PMID: 39542753 PMCID: PMC11960488 DOI: 10.1053/j.seminhematol.2024.10.009] [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: 08/05/2024] [Revised: 09/30/2024] [Accepted: 10/22/2024] [Indexed: 11/17/2024]
Abstract
Mutations in the tumor suppressor protein, TP53, lead to dismal outcomes in myeloid malignancies, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). Recent pathological reclassifications have integrated TP53 mutated MDS and AML under a unified category of TP53 mutated myeloid neoplasms, which allows for more flexibility in treatment approaches. Therapeutic strategies have predominantly mirrored those for AML, with allogeneic stem cell transplantation emerging as critical for long-term disease control. The question remains whether there are physiological distinctions within TP53 mutated myeloid neoplasms that will significantly impact prognosis and therapeutic considerations. This review explores the unique aspects of classically defined "TP53 mutated MDS", focusing on its distinct biological characteristics and outcomes. Our current understanding is that TP53 mutated MDS and AML are globally quite similar, but as a group have unique features compared to TP53 wildtype (WT) disease. Optimizing immunotherapy and targeting vulnerabilities due to co-mutations and/or chromosome abnormalities should be the focus of future research.
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Affiliation(s)
- Sarah Skuli
- Division of Hematology and Oncology, Department of Medicine, The University of Pennsylvania, Philadelphia, PA
| | - Andrew Matthews
- Division of Hematology and Oncology, Department of Medicine, The University of Pennsylvania, Philadelphia, PA
| | - Martin Carroll
- Division of Hematology and Oncology, Department of Medicine, The University of Pennsylvania, Philadelphia, PA
| | - Catherine Lai
- Division of Hematology and Oncology, Department of Medicine, The University of Pennsylvania, Philadelphia, PA.
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Lin Z, Assaraf YG, Kwok HF. Peptides for microbe-induced cancers: latest therapeutic strategies and their advanced technologies. Cancer Metastasis Rev 2024; 43:1315-1336. [PMID: 39008152 DOI: 10.1007/s10555-024-10197-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 06/14/2024] [Indexed: 07/16/2024]
Abstract
Cancer is a significant global health concern associated with multiple distinct factors, including microbial and viral infections. Numerous studies have elucidated the role of microorganisms, such as Helicobacter pylori (H. pylori), as well as viruses for example human papillomavirus (HPV), hepatitis B virus (HBV), and hepatitis C virus (HCV), in the development of human malignancies. Substantial attention has been focused on the treatment of these microorganism- and virus-associated cancers, with promising outcomes observed in studies employing peptide-based therapies. The current paper provides an overview of microbe- and virus-induced cancers and their underlying molecular mechanisms. We discuss an assortment of peptide-based therapies which are currently being developed, including tumor-targeting peptides and microbial/viral peptide-based vaccines. We describe the major technological advancements that have been made in the design, screening, and delivery of peptides as anticancer agents. The primary focus of the current review is to provide insight into the latest research and development in this field and to provide a realistic glimpse into the future of peptide-based therapies for microbe- and virus-induced neoplasms.
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Affiliation(s)
- Ziqi Lin
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR
| | - Yehuda G Assaraf
- The Fred Wyszkowski Cancer Research Lab, Faculty of Biology, Technion-Israel Instituteof Technology, Haifa, 3200003, Israel
| | - Hang Fai Kwok
- Cancer Centre, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR.
- Department of Biomedical Sciences, Faculty of Health Sciences, University of Macau, Avenida da Universidade, Taipa, Macau SAR.
- MoE Frontiers Science Center for Precision Oncology, University of Macau, Avenida de Universidade, Taipa, Macau SAR.
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38
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Zhang H, Xu J, Long Y, Maimaitijiang A, Su Z, Li W, Li J. Unraveling the Guardian: p53's Multifaceted Role in the DNA Damage Response and Tumor Treatment Strategies. Int J Mol Sci 2024; 25:12928. [PMID: 39684639 DOI: 10.3390/ijms252312928] [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: 10/29/2024] [Revised: 11/21/2024] [Accepted: 11/27/2024] [Indexed: 12/18/2024] Open
Abstract
DNA damage can lead to mutations that can alter the function of oncogenes or tumor suppressor genes, thus promoting the development of cancer. p53 plays a multifaceted and complex role in the DNA damage response and cancer progression and is known as the 'guardian of the gene'. When DNA damage occurs, p53 is activated through a series of post-translational modifications, which stabilize the protein and enhance its function as a transcription factor. It regulates processes including cell cycle checkpoints, DNA repair and apoptosis, thereby preventing the spread of damaged DNA and maintaining genome integrity. On the one hand, p53 can initiate cell cycle arrest and induce cells to enter the G1/S and G2/M checkpoints, preventing cells with damaged DNA from continuing to proliferate and gaining time for DNA repair. At the same time, p53 can promote the activation of DNA repair pathways, including base excision repair, nucleotide excision repair and other repair pathways, to ensure the integrity of genetic material. If the damage is too severe to repair, p53 will trigger the apoptosis process to eliminate potential cancer risks in time. p53 also plays a pivotal role in cancer progression. Mutations in the p53 gene are frequently found in many cancers, and the mutated p53 not only loses its normal tumor suppressor function but may even acquire pro-cancer activity. Therefore, we also discuss therapeutic strategies targeting the p53 pathway, such as the use of small-molecule drugs to restore the function of wild-type p53, the inhibition of negative regulatory factors and synthetic lethality approaches for p53-deficient tumors. This review therefore highlights the important role of p53 in maintaining genomic stability and its potential in therapeutic strategies for cancer.
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Affiliation(s)
- Han Zhang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China
| | - Jianxiong Xu
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China
| | - Yuxuan Long
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China
| | - Ayitila Maimaitijiang
- School of Pharmaceutical Science, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China
| | - Zhengding Su
- School of Pharmaceutical Science, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China
| | - Wenfang Li
- School of Pharmaceutical Science, Institute of Materia Medica, Xinjiang University, Urumqi 830017, China
| | - Jinyao Li
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, Urumqi 830017, China
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39
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Susanti R, Dafip M, Mustikaningtyas D, Putra A. Predictive action of oncomiR in suppressing TP53 signaling pathway in hypoxia-conditioned colon cancer cell line HCT-116. Cell Biol Int 2024; 48:1891-1905. [PMID: 39285519 DOI: 10.1002/cbin.12243] [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: 03/13/2024] [Revised: 05/09/2024] [Accepted: 08/31/2024] [Indexed: 11/15/2024]
Abstract
Hypoxia-induced heterogeneity in colorectal cancer (CRC) significantly impacts patient survival by promoting chemoresistance. These conditions alter the regulation of miRNAs, key regulators of crucial processes like proliferation, apoptosis, and invasion, leading to tumor progression. Despite their promising potential as diagnostic and therapeutic targets, the underlying mechanisms by which miRNAs influence hypoxia-mediated tumorigenesis remain largely unexplored. This study aims to elucidate the action of miRNAs in HCT-116 colorectal cancer stem cells (CSCs) under hypoxia, providing valuable insights into their role in tumor adaptation and progression. MiRNA expression was determined using Nanostring nCounter, and bioinformatic analysis was performed to explain the molecular pathway. A total of 50 miRNAs were obtained with an average count of ≥ 20 reads for comparative expression analysis. The results showed that hypoxia-affected 36 oncomiRs were increased in HCT-116, and 14 suppressor-miRs were increased in MSCs. The increase in miRNA expression occurred consistently from normoxia to hypoxia and significantly differed between mesenchymal stem cells (MSCs) and HCT-116. Furthermore, miR-16-5p and miR-29a-3p were dominant in regulating the p53 signaling pathway, which is thought to be related to the escape mechanism against hypoxia and maintaining cell proliferation. More research with a genome-transcriptome axis approach is needed to fully understand miRNAs' role in adapting CRC cells and MSCs to hypoxia. Further research could focus on developing specific biomarkers for diagnosis. In addition, anti-miR can be developed as a therapy to prevent cancer proliferation or inhibit the adaptation of cancer cells to hypoxia.
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Affiliation(s)
- R Susanti
- Department of Biology, Faculty of Mathematics and Natural Science, Universitas Negeri Semarang, Semarang, Indonesia
| | - Muchamad Dafip
- Department of Biology, Faculty of Mathematics and Natural Science, Universitas Negeri Semarang, Semarang, Indonesia
- Doctoral Program of Biotechnology, Postgraduate School, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Dewi Mustikaningtyas
- Department of Biology, Faculty of Mathematics and Natural Science, Universitas Negeri Semarang, Semarang, Indonesia
| | - Agung Putra
- Department of Biomedical Science, Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia
- Stem Cell and Cancer Research (SCCR), Faculty of Medicine, Universitas Islam Sultan Agung, Semarang, Indonesia
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40
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Li B, Sadagopan A, Li J, Wu Y, Cui Y, Konda P, Weiss CN, Choueiri TK, Doench JG, Viswanathan SR. A framework for target discovery in rare cancers. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.10.24.620074. [PMID: 39484513 PMCID: PMC11527139 DOI: 10.1101/2024.10.24.620074] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 11/03/2024]
Abstract
While large-scale functional genetic screens have uncovered numerous cancer dependencies, rare cancers are poorly represented in such efforts and the landscape of dependencies in many rare cancers remains obscure. We performed genome-scale CRISPR knockout screens in an exemplar rare cancer, TFE3-translocation renal cell carcinoma (tRCC), revealing previously unknown tRCC-selective dependencies in pathways related to mitochondrial biogenesis, oxidative metabolism, and kidney lineage specification. To generalize to other rare cancers in which experimental models may not be readily available, we employed machine learning to infer gene dependencies in a tumor or cell line based on its transcriptional profile. By applying dependency prediction to alveolar soft part sarcoma (ASPS), a distinct rare cancer also driven by TFE3 translocations, we discovered and validated that MCL1 represents a dependency in ASPS but not tRCC. Finally, we applied our model to predict gene dependencies in tumors from the TCGA (11,373 tumors; 28 lineages) and multiple additional rare cancers (958 tumors across 16 types, including 13 distinct subtypes of kidney cancer), nominating potentially actionable vulnerabilities in several poorly-characterized cancer types. Our results couple unbiased functional genetic screening with a predictive model to establish a landscape of candidate vulnerabilities across cancers, including several rare cancers currently lacking in potential targets.
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Affiliation(s)
- Bingchen Li
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
| | - Ananthan Sadagopan
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
| | - Jiao Li
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
| | - Yuqianxun Wu
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
| | - Yantong Cui
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
| | - Prathyusha Konda
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
| | - Cary N. Weiss
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
- Department of Pediatric Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
| | - Toni K. Choueiri
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School; Boston, MA 02215, USA
- Department of Medicine, Brigham and Women’s Hospital; Boston, MA 02215, USA
| | - John G. Doench
- Broad Institute of MIT and Harvard; Cambridge, MA 02142, USA
| | - Srinivas R. Viswanathan
- Department of Medical Oncology, Dana-Farber Cancer Institute; Boston, MA 02215, USA
- Department of Medicine, Harvard Medical School; Boston, MA 02215, USA
- Department of Medicine, Brigham and Women’s Hospital; Boston, MA 02215, USA
- Broad Institute of MIT and Harvard; Cambridge, MA 02142, USA
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41
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Ahmadi SE, Rahimian E, Rahimi S, Zarandi B, Bahraini M, Soleymani M, Safdari SM, Shabannezhad A, Jaafari N, Safa M. From regulation to deregulation of p53 in hematologic malignancies: implications for diagnosis, prognosis and therapy. Biomark Res 2024; 12:137. [PMID: 39538363 PMCID: PMC11565275 DOI: 10.1186/s40364-024-00676-9] [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: 07/16/2024] [Accepted: 10/22/2024] [Indexed: 11/16/2024] Open
Abstract
The p53 protein, encoded by the TP53 gene, serves as a critical tumor suppressor, playing a vital role in maintaining genomic stability and regulating cellular responses to stress. Dysregulation of p53 is frequently observed in hematological malignancies, significantly impacting disease progression and patient outcomes. This review aims to examine the regulatory mechanisms of p53, the implications of TP53 mutations in various hematological cancers, and emerging therapeutic strategies targeting p53. We conducted a comprehensive literature review to synthesize recent findings related to p53's multifaceted role in hematologic cancers, focusing on its regulatory pathways and therapeutic potential. TP53 mutations in hematological malignancies often lead to treatment resistance and poor prognosis. Current therapeutic strategies, including p53 reactivation and gene therapy, show promise in improving treatment outcomes. Understanding the intricacies of p53 regulation and the consequences of its mutations is essential for developing effective diagnostic and therapeutic strategies in hematological malignancies, ultimately enhancing patient care and survival.
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Affiliation(s)
- Seyed Esmaeil Ahmadi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Elahe Rahimian
- Department of Medical Translational Oncology, National Center for Tumor Diseases (NCT) Dresden, Dresden, Germany
| | - Samira Rahimi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Bahman Zarandi
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Mehran Bahraini
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Maral Soleymani
- Faculty of Medicine, Ahvaz Jundishapur University of Medical Sciences, Ahvaz, Iran
| | - Seyed Mehrab Safdari
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Ashkan Shabannezhad
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Niloofar Jaafari
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, 15261, USA
| | - Majid Safa
- Department of Hematology and Blood Banking, Faculty of Allied Medicine, Iran University of Medical Sciences, Tehran, Iran.
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42
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Sánchez-Castillo A, Kampen KR. Understanding serine and glycine metabolism in cancer: a path towards precision medicine to improve patient's outcomes. Discov Oncol 2024; 15:652. [PMID: 39538085 PMCID: PMC11561223 DOI: 10.1007/s12672-024-01544-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 11/06/2024] [Indexed: 11/16/2024] Open
Abstract
In this perspective, we highlight and reflect on the current knowledge with respect to serine/glycine metabolism in cancer, therapeutic resistance, and precision medicine opportunities for therapeutic targeting and treatment follow-up. Cancer subtypes with high mortality rates include lung cancer and glioblastomas. In order to improve future therapeutic opportunities, patient stratification need to be performed to select patients that might benefit from adjuvant serine/glycine targeting compounds. In an effort to identify the group of patients for stratification purposes, we analyzed publicly available TCGA patient datasets to test associations between serine/glycine metabolism enzyme expression and important cancer drivers in lung cancer and glioblastoma. These patients presenting serine/glycine pathway overexpression might benefit from adjuvant sertraline treatment in the future.
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Affiliation(s)
- Anaís Sánchez-Castillo
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht University, Maastricht, The Netherlands
| | - Kim R Kampen
- Department of Radiation Oncology (MAASTRO), GROW School for Oncology and Reproduction, Maastricht University Medical Center, Maastricht University, Maastricht, The Netherlands.
- Department of Oncology, Laboratory for Disease Mechanisms in Cancer, KU Leuven and Leuven Cancer Institute (LKI), Louvain, Belgium.
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Zhang LK, Li Y, Zhai L, Tang Y, Jiao Y, Mei Y, Yang R, You R, Yin L, Ni H, Ge J, Guan YQ. Natural Phycocyanin/Paclitaxel Micelle Delivery of Therapeutic P53 to Activate Apoptosis for HER2 or ER Positive Breast Cancer Therapy. ACS Biomater Sci Eng 2024; 10:6995-7004. [PMID: 39390952 DOI: 10.1021/acsbiomaterials.4c00756] [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: 10/12/2024]
Abstract
The P53 gene is commonly mutated in breast cancer, protein based the gene as anticancer drugs could provide efficient and stable advantages by restoring the function of the wild-type P53 protein. In this study, we describe the creation and utilization of a micelle composed by natural phycocyanin and paclitaxel and grafting anti-HER2 (PPH), which effectively packages and transports recombinant P53 protein with anti-ER (PE), resulting in a new entity designated as PE@PPH, to address localization obstacles and modify cellular tropism to the cell membrane or nucleus. The results indicate that PE@PPH has strong antitumor properties, even at low doses of PTX both in vitro and in vivo. These findings suggest that PE@PPH could be an enhancing micelle for delivering therapeutic proteins and promoting protein functional recovery, particularly in addressing the challenges posed by tumor heterogeneity in breast cancer.
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Affiliation(s)
- Ling-Kun Zhang
- School of Life Science, South China Normal University, Guangzhou 510631, China
- School of Engineering, Westlake University, Hangzhou 310030, China
- Institute of Advanced Technology, Westlake Institute for Advanced Study, Hangzhou, Zhejiang 310024, China
| | - Yuan Li
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Limin Zhai
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Yunzhi Tang
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Yuxuan Jiao
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Yitong Mei
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Runcai Yang
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China
| | - Rong You
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Liang Yin
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - He Ni
- School of Life Science, South China Normal University, Guangzhou 510631, China
| | - Jian Ge
- State Key Laboratory of Ophthalmology, Guangdong Provincial Key Laboratory of Ophthalmology and Visual Science, Zhongshan Ophthalmic Center, Sun Yat-sen University, Guangzhou, Guangdong 510060, China
| | - Yan-Qing Guan
- School of Life Science, South China Normal University, Guangzhou 510631, China
- MOE Key Laboratory of Laser Life Science & Institute of Laser Life Science, Guangdong Provincial Key Laboratory of Laser Life Science, Guangzhou Key Laboratory of Spectral Analysis and Functional Probes, College of Biophotonics, South China Normal University, Guangzhou 510631, China
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44
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Zhang L, Abro B, Campbell A, Ding Y. TP53 mutations in myeloid neoplasms: implications for accurate laboratory detection, diagnosis, and treatment. Lab Med 2024; 55:686-699. [PMID: 39001691 PMCID: PMC11532620 DOI: 10.1093/labmed/lmae048] [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: 11/05/2024] Open
Abstract
Genetic alterations that affect the function of p53 tumor suppressor have been extensively investigated in myeloid neoplasms, revealing their significant impact on disease progression, treatment response, and patient outcomes. The identification and characterization of TP53 mutations play pivotal roles in subclassifying myeloid neoplasms and guiding treatment decisions. Starting with the presentation of a typical case, this review highlights the complicated nature of genetic alterations involving TP53 and provides a comprehensive analysis of TP53 mutations and other alterations in myeloid neoplasms. Currently available methods used in clinical laboratories to identify TP53 mutations are discussed, focusing on the importance of establishing a robust testing protocol within clinical laboratories to ensure the delivery of accurate and reliable results. The treatment implications of TP53 mutations in myeloid neoplasms and clinical trial options are reviewed. Ultimately, we hope that this review provides valuable insights into the patterns of TP53 alterations in myeloid neoplasms and offers guidance to establish practical laboratory testing protocols to support the best practices of precision oncology.
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Affiliation(s)
- Linsheng Zhang
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, US
| | - Brooj Abro
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, US
| | - Andrew Campbell
- Department of Laboratory Medicine, Geisinger Medical Center, Danville, PA, US
| | - Yi Ding
- Department of Laboratory Medicine, Geisinger Medical Center, Danville, PA, US
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45
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Wang Y, Ding B, Tao Y, Huang L, Zhu Q, Gao C, Feng M, Han Y. Homologous recombination deficiency score is an independent prognostic factor in esophageal squamous cell carcinoma. J Pathol Clin Res 2024; 10:e70007. [PMID: 39469984 PMCID: PMC11519826 DOI: 10.1002/2056-4538.70007] [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: 06/21/2024] [Revised: 09/18/2024] [Accepted: 10/01/2024] [Indexed: 10/30/2024]
Abstract
Homologous recombination deficiency (HRD) represents an impairment in the homologous recombination repair (HRR) pathway, crucial for repairing DNA double-strand breaks and contributing to genomic instability in cancer. The HRD score may be a more reliable biomarker than HRR-related gene mutations for identifying patients sensitive to poly(ADP-ribose) polymerase inhibitors. Despite its relevance in various cancers, the HRD score remains underexplored in esophageal squamous cell carcinoma (ESCC). We retrospectively analyzed HRD scores in 96 ESCC patients, examining correlations with clinical characteristics and survival outcomes, and validated our findings using the TCGA dataset. Genomic sequencing utilized a custom superHRD next-generation sequencing panel, and HRD scores were calculated from 54,000 single-nucleotide polymorphisms using Kruskal-Wallis rank-sum tests and two cut-off points for analysis. Higher HRD scores correlated with advanced tumor stages, recurrence, and mutations in TP53 and ABCB1, while APC mutations were linked to lower HRD scores. Patients with high HRD scores had significantly shorter disease-free survival (p = 0.013) and a trend toward shorter overall survival (OS) (p = 0.005), particularly those not receiving adjuvant therapy. Conversely, HRD-high patients undergoing adjuvant therapy showed a trend toward longer OS (p = 0.015). Multivariate analysis identified HRD as an independent prognostic factor (hazard ratio = 2.814 for recurrence, p = 0.015). Validation with the TCGA dataset supported these findings. This study highlights the associations between HRD scores, clinical characteristics, and genomic mutations in ESCC, suggesting HRD as a potential prognostic biomarker. HRD assessment may aid in patient stratification and personalized treatment strategies, warranting further investigation to validate the therapeutic implications of HRD scores in ESCC.
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Affiliation(s)
- Yulu Wang
- Department of Pathology, Shanghai Chest Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiPR China
| | - Bowen Ding
- Department of Pathology, Shanghai Chest Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiPR China
| | - Yunlan Tao
- Department of Pathology, Shanghai Chest Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiPR China
| | - Lingli Huang
- Department of Pathology, Shanghai Chest Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiPR China
| | - Qian Zhu
- Department of Pathology, Shanghai Chest Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiPR China
| | - Chengying Gao
- Department of Pathology, Shanghai Chest Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiPR China
| | - Mingli Feng
- Department of Pathology, Shanghai Chest Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiPR China
| | - Yuchen Han
- Department of Pathology, Shanghai Chest Hospital, School of MedicineShanghai Jiaotong UniversityShanghaiPR China
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46
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Kopetz S, Murphy DA, Pu J, Ciardiello F, Desai J, Van Cutsem E, Wasan HS, Yoshino T, Saffari H, Zhang X, Hamilton P, Xie T, Yaeger R, Tabernero J. Molecular profiling of BRAF-V600E-mutant metastatic colorectal cancer in the phase 3 BEACON CRC trial. Nat Med 2024; 30:3261-3271. [PMID: 39313594 PMCID: PMC11564101 DOI: 10.1038/s41591-024-03235-9] [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: 01/10/2024] [Accepted: 08/06/2024] [Indexed: 09/25/2024]
Abstract
The BEACON CRC study demonstrated that encorafenib (Enco)+cetuximab (Cetux)±binimetinib (Bini) significantly improved overall survival (OS) versus Cetux + chemotherapy in previously treated patients with BRAF-V600E-mutant mCRC, providing the basis for the approval of the Enco+Cetux regimen in the United States and the European Union. A greater understanding of biomarkers predictive of response to Enco+Cetux±Bini treatment is of clinical relevance. In this prespecified, exploratory biomarker analysis of the BEACON CRC study, we characterize genomic and transcriptomic correlates of clinical outcomes and acquired resistance mechanisms through integrated clinical and molecular analysis, including whole-exome and -transcriptome tissue sequencing and circulating tumor DNA genomic profiling. Tumors with higher immune signatures showed a trend towards increased OS benefit with Enco+Bini+Cetux. RAS, MAP2K1 and MET alterations were most commonly acquired with Enco+Cetux±Bini, and more frequent in patients with a high baseline cell-cycle gene signature; baseline TP53 mutation was associated with acquired MET amplification. Acquired mutations were subclonal and polyclonal, with evidence of increased tumor mutation rate with Enco+Cetux±Bini and mutational signatures (SBS17a/b). These findings support treatment with Enco+Cetux±Bini for patients with BRAF-V600E-mutant mCRC and provide insights into the biology of response and resistance to MAPK-pathway-targeted therapy. ClinicalTrials.gov registration: NCT02928224.
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Affiliation(s)
- Scott Kopetz
- University of Texas MD Anderson Cancer Center, Houston, TX, USA.
| | | | - Jie Pu
- Pfizer, New York, NY, USA
| | | | - Jayesh Desai
- Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia
| | - Eric Van Cutsem
- University Hospitals Gasthuisberg Leuven and KU Leuven, Leuven, Belgium
| | | | | | | | | | | | | | - Rona Yaeger
- Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Josep Tabernero
- Vall d'Hebron Hospital Campus and Vall d'Hebron Institute of Oncology (VHIO), University of Vic-Central University of Catalonia, Barcelona, Spain
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47
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Luo Y, Liang H. Developmental-status-aware transcriptional decomposition establishes a cell state panorama of human cancers. Genome Med 2024; 16:124. [PMID: 39468667 PMCID: PMC11514945 DOI: 10.1186/s13073-024-01393-6] [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: 05/10/2023] [Accepted: 10/03/2024] [Indexed: 10/30/2024] Open
Abstract
BACKGROUND Cancer cells evolve under unique functional adaptations that unlock transcriptional programs embedded in adult stem and progenitor-like cells for progression, metastasis, and therapeutic resistance. However, it remains challenging to quantify the stemness-aware cell state of a tumor based on its gene expression profile. METHODS We develop a developmental-status-aware transcriptional decomposition strategy using single-cell RNA-sequencing-derived tissue-specific fetal and adult cell signatures as anchors. We apply our method to various biological contexts, including developing human organs, adult human tissues, experimentally induced differentiation cultures, and bulk human tumors, to benchmark its performance and to reveal novel biology of entangled developmental signaling in oncogenic processes. RESULTS Our strategy successfully captures complex dynamics in developmental tissue bulks, reveals remarkable cellular heterogeneity in adult tissues, and resolves the ambiguity of cell identities in in vitro transformations. Applying it to large patient cohorts of bulk RNA-seq, we identify clinically relevant cell-of-origin patterns and observe that decomposed fetal cell signals significantly increase in tumors versus normal tissues and metastases versus primary tumors. Across cancer types, the inferred fetal-state strength outperforms published stemness indices in predicting patient survival and confers substantially improved predictive power for therapeutic responses. CONCLUSIONS Our study not only provides a general approach to quantifying developmental-status-aware cell states of bulk samples but also constructs an information-rich, biologically interpretable, cell-state panorama of human cancers, enabling diverse translational applications.
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Affiliation(s)
- Yikai Luo
- Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, 77030, USA
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
- Division of Rheumatology, Department of Medicine, University of California, San Francisco, San Francisco, CA, 94143, USA
| | - Han Liang
- Graduate Program in Quantitative and Computational Biosciences, Baylor College of Medicine, Houston, TX, 77030, USA.
- Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Department of Systems Biology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
- Institute for Data Science in Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
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48
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Quan S, Li N, Lian S, Wang Y, Liu Y, Liu J, Zhang Z, Gao D, Li Y. SLC4A4 as a novel biomarker involved in immune system response and lung adenocarcinoma progression. Int Immunopharmacol 2024; 140:112756. [PMID: 39083932 DOI: 10.1016/j.intimp.2024.112756] [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: 05/07/2024] [Revised: 07/14/2024] [Accepted: 07/22/2024] [Indexed: 08/02/2024]
Abstract
BACKGROUND Altered expression and activity of solute carrier family 4 member 4 (SLC4A4) could affect the growth, survival and metastasis of tumor cells. Currently, the role of SLC4A4 in lung adenocarcinoma (LUAD) immunotherapy and prognosis was not entirely clear. METHODS We analyzed SLC4A4 expression in LUAD tissues and cell lines using quantitative reverse transcription-polymerase chain reaction, Western blotting, and immunohistochemistry. The effects of SLC4A4 overexpression on angiogenesis, cell migration, invasion, and epithelial-mesenchymal transition were examined. Public databases helped construct a risk model evaluating SLC4A4's expression on LUAD prognosis and immunotherapy response. Additionally, a xenograft model, flow cytometry, and enzyme-linked immunosorbent assay further explored SLC4A4's role in tumor immune microenvironment infiltration. RESULTS Upregulation of SLC4A4 promoted apoptosis in the LUAD cell line and significantly inhibited the migration and invasive ability of cancer cells (P<0.01). A total of 10 key genes (including SIGLEC6, RHOV, PIR, MOB3B, MIR3135B, LPAR6, KRT8, ITGA2, CPS1, and C6) were screened according to SLC4A4 expression, immune score and stromal score, and a prognostic model with good outcome was constructed (AUC values of which in the training cohort at 1,3, and 5 years reached 0.73, 0.73, and 0.72, respectively). Importantly, we demonstrated that high expression of SLC4A4 was able to increase the proliferation level and cytokine secretion of CD8+ T cells for the purpose of promoting the immune system response to LUAD. CONCLUSION Our study revealed that SLC4A4 can serve as a prognostic indicator for LUAD, providing new insights into the treatment and diagnosis of LUAD.
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Affiliation(s)
- Siyu Quan
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China
| | - Na Li
- Nephrology Department, Jinan Zhangqiu District People's Hospital, Jinan 250200, China
| | - Shihai Lian
- Out-patient Department, Zaozhuang Municipal Hospital, Zaozhuang 277102, China
| | - Yuanyuan Wang
- The Department of Hospital Infection, Jinan Fifth People's Hospital, Jinan 250022, China
| | - Yang Liu
- Thoracic Surgery, PLA 80th Group Army Hospital, Weifang 261011, China
| | - Jianbo Liu
- Department of Thoracic Surgery, The Fourth People's Hospital of Heze, Heze 274100, China
| | - Zewei Zhang
- Department of Thoracic Surgery, Gaoqing County People's Hospital, Gaoqing 256399, China
| | - Dejun Gao
- Department of Thoracic Surgery, The Second People's Hospital of Liaocheng, Liaocheng 252600, China
| | - Yun Li
- Department of Thoracic Surgery, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan 250021, China.
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49
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Zheng J, Xu F, Li G, Lin M, Hao H. The value of chromosome instability detected by low-pass whole-genome sequencing in preoperative prediction of sentinel lymph node metastasis in breast cancer. Front Oncol 2024; 14:1434526. [PMID: 39429474 PMCID: PMC11486760 DOI: 10.3389/fonc.2024.1434526] [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: 05/18/2024] [Accepted: 09/05/2024] [Indexed: 10/22/2024] Open
Abstract
Background Breast cancer is a malignancy characterized by chromosomal instability (CIN). This study aimed to examine the potential diagnostic value of chromosomal instability, detected by low-pass whole-genome sequencing (LPWGS), in the preoperative evaluation of sentinel lymph node metastasis (SLNM) in breast cancer. Methods A retrospective investigation of clinical records from 29 patients with breast cancer revealed two distinct groups based on sentinel lymph node biopsy (SLNB) results: the SLN metastasis group (24 cases) and the SLN non-metastasis group (five cases). CIN and CIN scores were evaluated using LPWGS. An analysis of univariate data and binary logistic regression was employed to identify factors influencing SLNM, and a curve with receiver operating characteristics (ROC) was constructed to assess the diagnostic utility of CIN in predicting SLNM. Results A significant association between the SLNM and CIN high groups was observed in breast cancer (P=0.011). The CIN score in the metastasis group (17,665.055 ± 8,630.691) was higher than that in the non-metastasis group (9,247.973 ± 3,692.873), demonstrating a significant difference (P=0.044). Univariate binary logistic regression analysis indicated that CIN was a significant predictor for SLNM (odds ratio: 4.036, 95% CI: 1.015-16.047, P=0.048). The AUC of CIN for preoperative diagnosis of SLNM was 0.808 (95%CI: 0.635-0.982, P=0.033), with a sensitivity value of 67.0% and specificity of 100.0% at a threshold of 13,563. Conclusion Detecting CIN through LPWGS demonstrates diagnostic potential in predicting SLNM in patients with breast cancer before surgery. This approach offers a novel method for assessing axillary lymph node status in clinical practice.
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Affiliation(s)
- Jian Zheng
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Fen Xu
- Department of General Medicine, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Guangying Li
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Moubin Lin
- Department of General Surgery, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
| | - Hua Hao
- Department of Pathology, Yangpu Hospital, School of Medicine, Tongji University, Shanghai, China
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Bakhtiar H, Sharifi MN, Helzer KT, Shi Y, Bootsma ML, Shang TA, Chrostek MR, Berg TJ, Carson Callahan S, Carreno V, Blitzer GC, West MT, O'Regan RM, Wisinski KB, Sjöström M, Zhao SG. A phenocopy signature of TP53 loss predicts response to chemotherapy. NPJ Precis Oncol 2024; 8:220. [PMID: 39358429 PMCID: PMC11447220 DOI: 10.1038/s41698-024-00722-7] [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: 04/02/2024] [Accepted: 09/22/2024] [Indexed: 10/04/2024] Open
Abstract
In preclinical studies, p53 loss of function impacts chemotherapy response, but this has not been consistently validated clinically. We trained a TP53-loss phenocopy gene expression signature from pan-cancer clinical samples in the TCGA. In vitro, the TP53-loss phenocopy signature predicted chemotherapy response across cancer types. In a clinical dataset of 3003 breast cancer samples treated with neoadjuvant chemotherapy, the TP53-loss phenocopy samples were 56% more likely to have a pathologic complete response (pCR), with a significant association between TP53-loss phenocopy and pCR in both ER positive and ER negative tumors. In an independent clinical validation in the I-SPY2 trial (N = 987), we confirmed the association with neoadjuvant chemotherapy pCR and found higher rates of chemoimmunotherapy response in TP53-loss phenocopy tumors compared to non-TP53-loss phenocopy tumors (64% vs. 28%). The TP53-loss phenocopy signature predicts chemotherapy response across cancer types in vitro, and in a proof-of-concept clinical validation is associated with neoadjuvant chemotherapy response across multiple clinical breast cancer cohorts.
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Affiliation(s)
- Hamza Bakhtiar
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Marina N Sharifi
- Department of Medicine, Division of Hematology, Oncology, and Palliative Care, University of Wisconsin, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
| | - Kyle T Helzer
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Yue Shi
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Matthew L Bootsma
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Tianfu A Shang
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | | | - Tracy J Berg
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - S Carson Callahan
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Viridiana Carreno
- Department of Medicine, Division of Hematology, Oncology, and Palliative Care, University of Wisconsin, Madison, WI, USA
| | - Grace C Blitzer
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA
| | - Malinda T West
- Department of Medicine, Division of Hematology, Oncology, and Palliative Care, University of Wisconsin, Madison, WI, USA
| | - Ruth M O'Regan
- Department of Medicine, University of Rochester, Rochester, NY, USA
| | - Kari B Wisinski
- Department of Medicine, Division of Hematology, Oncology, and Palliative Care, University of Wisconsin, Madison, WI, USA
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA
| | - Martin Sjöström
- Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, 94143, USA
| | - Shuang G Zhao
- Department of Human Oncology, University of Wisconsin, Madison, WI, USA.
- Carbone Cancer Center, University of Wisconsin, Madison, WI, USA.
- William S. Middleton Memorial Veterans Hospital, Madison, WI, USA.
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