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Smith SC, Melson JW, Quillin JM, Hiemenz MC, Tomlins SA, Wobker SE. A pathologist's primer on implementing new standard-of-care molecular biomarker testing for precision prostate cancer management. Am J Clin Pathol 2025; 163:649-655. [PMID: 39838622 DOI: 10.1093/ajcp/aqae186] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/18/2024] [Accepted: 12/27/2024] [Indexed: 01/23/2025] Open
Affiliation(s)
- Steven C Smith
- Departments of Pathology and Surgery, VCU School of Medicine, VCU Massey Comprehensive Cancer Center, and Richmond VA Medical Center, Richmond, VA, United States
| | - John W Melson
- Department of Medicine, VCU School of Medicine and VCU Massey Comprehensive Cancer Center, Richmond, VA, United States
| | - John M Quillin
- Department of Pediatrics, VCU School of Medicine, Richmond, VA, United States
| | | | - Scott A Tomlins
- Strata Oncology and Departments of Pathology and Urology, University of Michigan Medical School, Ann Arbor, MI, United States
| | - Sara E Wobker
- Department of Pathology and Laboratory Medicine, University of North Carolina, Chapel Hill, NC, United States
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2
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Tufail M, Jiang CH, Li N. Wnt signaling in cancer: from biomarkers to targeted therapies and clinical translation. Mol Cancer 2025; 24:107. [PMID: 40170063 PMCID: PMC11963613 DOI: 10.1186/s12943-025-02306-w] [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: 02/04/2025] [Accepted: 03/15/2025] [Indexed: 04/03/2025] Open
Abstract
The Wnt signaling pathway plays a crucial role in development and tissue homeostasis, regulating key cellular processes such as proliferation, differentiation, and apoptosis. However, its abnormal activation is strongly associated with tumorigenesis, metastasis, and resistance to therapy, making it a vital target for cancer treatment. This review provides a comprehensive insight into the role of Wnt signaling in cancer, examining its normal physiological functions, dysregulation in malignancies, and therapeutic potential. We emphasize the importance of predicting Wnt signaling sensitivity and identify key biomarkers across various cancer types. Additionally, we address the challenges and future prospects of Wnt-targeted therapies, including biomarker discovery, advancements in emerging technologies, and their application in clinical practice.
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Affiliation(s)
- Muhammad Tufail
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
| | - Can-Hua Jiang
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China
| | - Ning Li
- Department of Oral and Maxillofacial Surgery, Center of Stomatology, Xiangya Hospital, Central South University, Changsha, China.
- Institute of Oral Precancerous Lesions, Central South University, Changsha, China.
- Research Center of Oral and Maxillofacial Tumor, Xiangya Hospital, Central South University, Changsha, China.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, China.
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3
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Furtado LV, Ikemura K, Benkli CY, Moncur JT, Huang RSP, Zehir A, Stellato K, Vasalos P, Sadri N, Suarez CJ. General Applicability of Existing College of American Pathologists Accreditation Requirements to Clinical Implementation of Machine Learning-Based Methods in Molecular Oncology Testing. Arch Pathol Lab Med 2025; 149:319-327. [PMID: 38871357 DOI: 10.5858/arpa.2024-0037-cp] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/07/2024] [Indexed: 06/15/2024]
Abstract
CONTEXT.— The College of American Pathologists (CAP) accreditation requirements for clinical laboratory testing help ensure laboratories implement and maintain systems and processes that are associated with quality. Machine learning (ML)-based models share some features of conventional laboratory testing methods. Accreditation requirements that specifically address clinical laboratories' use of ML remain in the early stages of development. OBJECTIVE.— To identify relevant CAP accreditation requirements that may be applied to the clinical adoption of ML-based molecular oncology assays, and to provide examples of current and emerging ML applications in molecular oncology testing. DESIGN.— CAP accreditation checklists related to molecular pathology and general laboratory practices (Molecular Pathology, All Common and Laboratory General) were reviewed. Examples of checklist requirements that are generally applicable to validation, revalidation, quality management, infrastructure, and analytical procedures of ML-based molecular oncology assays were summarized. Instances of ML use in molecular oncology testing were assessed from literature review. RESULTS.— Components of the general CAP accreditation framework that exist for traditional molecular oncology assay validation and maintenance are also relevant for implementing ML-based tests in a clinical laboratory. Current and emerging applications of ML in molecular oncology testing include DNA methylation profiling for central nervous system tumor classification, variant calling, microsatellite instability testing, mutational signature analysis, and variant prediction from histopathology images. CONCLUSIONS.— Currently, much of the ML activity in molecular oncology is within early clinical implementation. Despite specific considerations that apply to the adoption of ML-based methods, existing CAP requirements can serve as general guidelines for the clinical implementation of ML-based assays in molecular oncology testing.
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Affiliation(s)
- Larissa V Furtado
- From the Department of Pathology, St. Jude Children's Research Hospital, Memphis, Tennessee (Furtado)
| | - Kenji Ikemura
- the Department of Pathology, Mass General Brigham, Boston, Massachusetts (Ikemura)
| | - Cagla Y Benkli
- the Department of Pathology, Baylor College of Medicine, Houston, Texas (Benkli)
| | - Joel T Moncur
- Office of the Director, The Joint Pathology Center, Silver Spring, Maryland (Moncur)
| | - Richard S P Huang
- Clinical Development, Foundation Medicine Inc, Cambridge, Massachusetts (Huang)
| | - Ahmet Zehir
- Precision Medicine & Biosamples, AstraZeneca, New York, New York (Zehir)
| | - Katherine Stellato
- Proficiency Testing, College of American Pathologists, Northfield, Illinois (Stellato, Vasalos)
| | - Patricia Vasalos
- Proficiency Testing, College of American Pathologists, Northfield, Illinois (Stellato, Vasalos)
| | - Navid Sadri
- the Department of Pathology, University Hospitals Cleveland Medical Center, Cleveland, Ohio (Sadri)
| | - Carlos J Suarez
- the Department of Pathology, Stanford University School of Medicine, Palo Alto, California (Suarez)
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Wang CW, Muzakky H, Lee YC, Chung YP, Wang YC, Yu MH, Wu CH, Chao TK. Interpretable multi-stage attention network to predict cancer subtype, microsatellite instability, TP53 mutation and TMB of endometrial and colorectal cancer. Comput Med Imaging Graph 2025; 121:102499. [PMID: 39947084 DOI: 10.1016/j.compmedimag.2025.102499] [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: 10/15/2024] [Revised: 12/12/2024] [Accepted: 01/22/2025] [Indexed: 03/03/2025]
Abstract
Mismatch repair deficiency (dMMR), also known as high-grade microsatellite instability (MSI-H), is a well-established biomarker for predicting the immunotherapy response in endometrial cancer (EC) and colorectal cancer (CRC). Tumor mutational burden (TMB) has also emerged as an important quantitative genomic biomarker for assessing the efficacy of immune checkpoint inhibitors. Although next-generation sequencing (NGS) can be used to assess MSI and TMB, the high costs, low sample throughput, and significant DNA requirements make NGS impractical for routine clinical screening. In this study, an interpretable, multi-stage attention deep learning (DL) network is introduced to predict pathological subtypes, MSI, TP53 mutations, and TMB directly from low-cost, routinely used histopathological whole slide images of EC and CRC slides. Experimental results showed that this method consistently outperformed seven state-of-the-art approaches in cancer subtyping and molecular status prediction across EC and CRC datasets. Fisher's Least Significant Difference test confirmed a strong correlation between model predictions and actual molecular statuses (MSI, TP53, and TMB) (p<0.001). Furthermore, Kaplan-Meier disease-free survival analysis revealed that CRC patients with model-predicted high TMB had significantly longer disease-free survival than those with low TMB (p<0.05). These findings demonstrate that the proposed DL-based approach holds significant potential for directly predicting immunotherapy-related pathological diagnoses and molecular statuses from routine WSIs, supporting personalized cancer immunotherapy treatment decisions in EC and CRC.
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Affiliation(s)
- Ching-Wei Wang
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan.
| | - Hikam Muzakky
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan
| | - Yu-Ching Lee
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan
| | - Yu-Pang Chung
- Graduate Institute of Biomedical Engineering, National Taiwan University of Science and Technology, Taipei, Taiwan
| | - Yu-Chi Wang
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei, Taiwan; Department of Gynecology and Obstetrics, National Defense Medical Center, Taipei, Taiwan
| | - Mu-Hsien Yu
- Department of Gynecology and Obstetrics, Tri-Service General Hospital, Taipei, Taiwan; Department of Gynecology and Obstetrics, National Defense Medical Center, Taipei, Taiwan
| | - Chia-Hua Wu
- Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan
| | - Tai-Kuang Chao
- Department of Pathology, Tri-Service General Hospital, Taipei, Taiwan; Institute of Pathology and Parasitology, National Defense Medical Center, Taipei, Taiwan.
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5
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Hwang T, Sitko L, Khoirunnisa R, Navarro-Aguad F, Samuel D, Park H, Cheon B, Mutsnaini L, Lee J, Otlu B, Takeda S, Lee S, Ivanov D, Gartner A. Comprehensive whole-genome sequencing reveals origins of mutational signatures associated with aging, mismatch repair deficiency and temozolomide chemotherapy. Nucleic Acids Res 2025; 53:gkae1122. [PMID: 39656916 PMCID: PMC11724276 DOI: 10.1093/nar/gkae1122] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2024] [Revised: 10/17/2024] [Accepted: 11/07/2024] [Indexed: 12/17/2024] Open
Abstract
In a comprehensive study to decipher the multi-layered response to the chemotherapeutic agent temozolomide (TMZ), we analyzed 427 genomes and determined mutational patterns in a collection of ∼40 isogenic DNA repair-deficient human TK6 lymphoblast cell lines. We first demonstrate that the spontaneous mutational background is very similar to the aging-associated mutational signature SBS40 and mainly caused by polymerase zeta-mediated translesion synthesis (TLS). MSH2-/- mismatch repair (MMR) knockout in conjunction with additional repair deficiencies uncovers cryptic mutational patterns. We next report how distinct mutational signatures are induced by TMZ upon sequential inactivation of DNA repair pathways, mirroring the acquisition of chemotherapy resistance by glioblastomas. The most toxic adduct induced by TMZ, O6-meG, is directly repaired by the O6-methylguanine-DNA methyltransferase (MGMT). In MGMT-/- cells, MMR leads to cell death and limits mutagenesis. MMR deficiency results in TMZ resistance, allowing the accumulation of ∼105 C > T substitutions corresponding to signature SBS11. Under these conditions, N3-methyladenine (3-meA), processed by base excision repair (BER), limits cell survival. Without BER, 3-meA is read through via error-prone TLS, causing T > A substitutions but not affecting survival. Blocking BER after abasic site formation results in large deletions and TMZ hypersensitization. Our findings reveal potential vulnerabilities of TMZ-resistant tumors.
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Affiliation(s)
- Taejoo Hwang
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Republic of Korea
| | - Lukasz Karol Sitko
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan 44919, Republic of Korea
- Center for Genomic Integrity, Institute for Basic Science, UNIST-gil 50, Ulsan 44919, Republic of Korea
| | - Ratih Khoirunnisa
- Center for Genomic Integrity, Institute for Basic Science, UNIST-gil 50, Ulsan 44919, Republic of Korea
| | - Fernanda Navarro-Aguad
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan 44919, Republic of Korea
- Center for Genomic Integrity, Institute for Basic Science, UNIST-gil 50, Ulsan 44919, Republic of Korea
| | - David M Samuel
- Center for Genomic Integrity, Institute for Basic Science, UNIST-gil 50, Ulsan 44919, Republic of Korea
| | - Hajoong Park
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan 44919, Republic of Korea
- Center for Genomic Integrity, Institute for Basic Science, UNIST-gil 50, Ulsan 44919, Republic of Korea
| | - Banyoon Cheon
- Center for Genomic Integrity, Institute for Basic Science, UNIST-gil 50, Ulsan 44919, Republic of Korea
| | - Luthfiyyah Mutsnaini
- Center for Genomic Integrity, Institute for Basic Science, UNIST-gil 50, Ulsan 44919, Republic of Korea
| | - Jaewoong Lee
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Republic of Korea
| | - Burçak Otlu
- Department of Health Informatics, Graduate School of Informatics, Middle East Technical University, Ankara, Turkey
| | - Shunichi Takeda
- Guangdong Key Laboratory for Genome Stability & Disease Prevention, Shenzhen University Medical School, 1066 Xueyuan Avenue, Shenzhen, Guangdong 518060, China
| | - Semin Lee
- Department of Biomedical Engineering, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Republic of Korea
| | - Dmitri Ivanov
- Center for Genomic Integrity, Institute for Basic Science, UNIST-gil 50, Ulsan 44919, Republic of Korea
| | - Anton Gartner
- Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan 44919, Republic of Korea
- Center for Genomic Integrity, Institute for Basic Science, UNIST-gil 50, Ulsan 44919, Republic of Korea
- Graduate School for Health Sciences and Technology, Ulsan National Institute of Science and Technology (UNIST), UNIST-gil 50, Ulsan, 44919, Republic of Korea
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Kehmann L, Jördens M, Loosen SH, Luedde T, Roderburg C, Leyh C. Evolving therapeutic landscape of advanced biliary tract cancer: from chemotherapy to molecular targets. ESMO Open 2024; 9:103706. [PMID: 39366294 PMCID: PMC11489061 DOI: 10.1016/j.esmoop.2024.103706] [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: 03/26/2024] [Revised: 08/07/2024] [Accepted: 08/12/2024] [Indexed: 10/06/2024] Open
Abstract
Biliary tract cancer, the second most common type of liver cancer, remains a therapeutic challenge due to its late diagnosis and poor prognosis. In recent years, it has become evident that classical chemotherapy might not be the optimal treatment for patients with biliary tract cancer, especially after failure of first-line therapy. Finding new treatment options and strategies to improve the survival of these patients is therefore crucial. With the rise and increasing availability of genetic testing in patients with tumor, novel treatment approaches targeting specific genetic alterations have recently been proposed and have demonstrated their safety and efficacy in numerous clinical trials. In this review, we will first consider chemotherapy options and the new possibility of combining chemotherapy with immune checkpoint inhibitors in first-line treatment. We will then provide an overview of genomic alterations and their potential for targeted therapy especially in second-line therapy. In addition to the most common alterations such as isocitrate dehydrogenase 1 or 2 (IDH1/2) mutations, fibroblast growth factor receptor 2 (FGFR2) fusions, and alterations, we will also discuss less frequently encountered alterations such as BRAF V600E mutation and neurotrophic tyrosine kinase receptor gene (NTRK) fusion. We highlight the importance of molecular profiling in guiding therapeutic decisions and emphasize the need for continued research to optimize and expand targeted treatment strategies for this aggressive malignancy.
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Affiliation(s)
- L Kehmann
- Department of Hepatology and Gastroenterology, Campus Virchow Klinikum, Charité University Medicine Berlin, Berlin, Germany; Servier Deutschland GmbH, München, Germany
| | - M Jördens
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - S H Loosen
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - T Luedde
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - C Roderburg
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany
| | - C Leyh
- Clinic of Gastroenterology, Hepatology & Infectious Diseases, Medical Faculty and University Hospital of Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany; Center for Integrated Oncology Aachen Bonn Cologne Düsseldorf (CIO ABCD), Düsseldorf, Germany.
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7
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Dong F. Pan-Cancer Molecular Biomarkers: A Paradigm Shift in Diagnostic Pathology. Clin Lab Med 2024; 44:325-337. [PMID: 38821647 DOI: 10.1016/j.cll.2023.08.013] [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: 06/02/2024]
Abstract
The rapid adoption of next-generation sequencing in clinical oncology has enabled the detection of molecular biomarkers shared between multiple tumor types. These pan-cancer biomarkers include sequence-altering mutations, copy number changes, gene rearrangements, and mutational signatures and have been demonstrated to predict response to targeted therapy. This article reviews issues surrounding current and emerging pan-cancer molecular biomarkers in clinical oncology: technological advances that enable the broad detection of cancer mutations across hundreds of genes, the spectrum of driver and passenger mutations derived from human cancer genomes, and implications for patient care now and in the near future.
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Affiliation(s)
- Fei Dong
- Department of Pathology, Stanford University School of Medicine, 3375 Hillview Ave, Palo Alto, CA 94304, USA.
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Galant N, Krawczyk P, Monist M, Obara A, Gajek Ł, Grenda A, Nicoś M, Kalinka E, Milanowski J. Molecular Classification of Endometrial Cancer and Its Impact on Therapy Selection. Int J Mol Sci 2024; 25:5893. [PMID: 38892080 PMCID: PMC11172295 DOI: 10.3390/ijms25115893] [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: 04/17/2024] [Revised: 05/21/2024] [Accepted: 05/27/2024] [Indexed: 06/21/2024] Open
Abstract
Endometrial cancer (EC) accounts for 90% of uterine cancer cases. It is considered not only one of the most common gynecological malignancies but also one of the most frequent cancers among women overall. Nowadays, the differentiation of EC subtypes is based on immunohistochemistry and molecular techniques. It is considered that patients' prognosis and the implementation of the appropriate treatment depend on the cancer subtype. Patients with pathogenic variants in POLE have the most favorable outcome, while those with abnormal p53 protein have the poorest. Therefore, in patients with POLE mutation, the de-escalation of postoperative treatment may be considered, and patients with abnormal p53 protein should be subjected to intensive adjuvant therapy. Patients with a DNA mismatch repair (dMMR) deficiency are classified in the intermediate prognosis group as EC patients without a specific molecular profile. Immunotherapy has been recognized as an effective treatment method in patients with advanced or recurrent EC with a mismatch deficiency. Thus, different adjuvant therapy approaches, including targeted therapy and immunotherapy, are being proposed depending on the EC subtype, and international guidelines, such as those published by ESMO and ESGO/ESTRO/ESP, include recommendations for performing the molecular classification of all EC cases. The decision about adjuvant therapy selection has to be based not only on clinical data and histological type and stage of cancer, but, following international recommendations, has to include EC molecular subtyping. This review describes how molecular classification could support more optimal therapeutic management in endometrial cancer patients.
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Affiliation(s)
- Natalia Galant
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-090 Lublin, Poland; (N.G.); (P.K.); (M.N.); (J.M.)
| | - Paweł Krawczyk
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-090 Lublin, Poland; (N.G.); (P.K.); (M.N.); (J.M.)
| | - Marta Monist
- II Department of Gynecology, Medical University of Lublin, 20-090 Lublin, Poland;
| | - Adrian Obara
- Institute of Genetics and Immunology GENIM LCC, 20-609 Lublin, Poland; (A.O.); (Ł.G.)
| | - Łukasz Gajek
- Institute of Genetics and Immunology GENIM LCC, 20-609 Lublin, Poland; (A.O.); (Ł.G.)
| | - Anna Grenda
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-090 Lublin, Poland; (N.G.); (P.K.); (M.N.); (J.M.)
| | - Marcin Nicoś
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-090 Lublin, Poland; (N.G.); (P.K.); (M.N.); (J.M.)
| | - Ewa Kalinka
- Department of Oncology, Polish Mother’s Memorial Hospital-Research Institute, 93-338 Łódź, Poland;
| | - Janusz Milanowski
- Department of Pneumonology, Oncology and Allergology, Medical University of Lublin, 20-090 Lublin, Poland; (N.G.); (P.K.); (M.N.); (J.M.)
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Evrard C, Cortes U, Ndiaye B, Bonnemort J, Martel M, Aguillon R, Tougeron D, Karayan-Tapon L. An Innovative and Accurate Next-Generation Sequencing-Based Microsatellite Instability Detection Method for Colorectal and Endometrial Tumors. J Transl Med 2024; 104:100297. [PMID: 38008183 DOI: 10.1016/j.labinv.2023.100297] [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: 04/12/2023] [Revised: 11/20/2023] [Accepted: 11/20/2023] [Indexed: 11/28/2023] Open
Abstract
The detection of microsatellite instability (MSI) and mismatch repair (MMR) deficiency has become mandatory for most tumors in recent years, owing to the development of immune checkpoint inhibitors as a highly effective therapy for MMR deficiency/MSI tumors. The timely and efficient detection of MSI is valuable, and new methods are increasingly being developed. To date, MMR assessment has been performed using immunohistochemistry of the 4 MMR proteins and/or microsatellite stability/MSI using PCR, mostly using the pentaplex panel. The implementation of next-generation sequencing (NGS) for MSI analysis would improve the effectiveness at a lower cost and in less time. This study describes the development of 8 new microsatellites combined with a classification algorithm, termed "Octaplex CaBio-MSID" (for Cancérologie Biologique MSI Detection tool), to assess MSI using NGS. A series of 303 colorectal cancer and 88 endometrial cancer samples were assessed via MSI testing using NGS using the Octaplex CaBio-MSID algorithm. The sensitivity and specificity of Octaplex CaBio-MSID were 98.4% and 98.4% for colorectal cancers, and 89.3% and 100% for endometrial cancers, respectively. This new NGS-based MSI detection method outperforms previously published methods (ie, Idylla [Biocartis], OncoMate MSI Dx [Promega], and Foundation One CDx [Roche Foundation Medicine]). Although highly efficient, Octaplex CaBio-MSID requires validation in a larger independent series of different tumor types.
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Affiliation(s)
- Camille Evrard
- Université de Poitiers, PRoDiCeT, Poitiers, France; CHU de Poitiers, Service d'Oncologie médicale, Poitiers, France.
| | - Ulrich Cortes
- CHU de Poitiers, Service de Cancérologie Biologique, Poitiers, France
| | - Birama Ndiaye
- CHU de Poitiers, Service de Cancérologie Biologique, Poitiers, France
| | | | - Marine Martel
- CHU de Poitiers, Service de Cancérologie Biologique, Poitiers, France
| | - Roxanne Aguillon
- CHU de Poitiers, Service de Cancérologie Biologique, Poitiers, France
| | - David Tougeron
- Université de Poitiers, PRoDiCeT, Poitiers, France; CHU de Poitiers, Service d'hépato-Gastro-Entérologie, Poitiers, France
| | - Lucie Karayan-Tapon
- Université de Poitiers, PRoDiCeT, Poitiers, France; CHU de Poitiers, Service de Cancérologie Biologique, Poitiers, France
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10
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Ortendahl JD, Cuyun Carter G, Thakkar SG, Bognar K, Hall DW, Abdou Y. Value of next generation sequencing (NGS) testing in advanced cancer patients. J Med Econ 2024; 27:519-530. [PMID: 38466204 DOI: 10.1080/13696998.2024.2329009] [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: 11/06/2023] [Accepted: 03/07/2024] [Indexed: 03/12/2024]
Abstract
OBJECTIVE The availability of targeted therapies for oncology patients is increasing. Available genomic tests to identify treatment-eligible patients include single gene tests and gene panel tests, including the whole-exome, whole-transcriptome OncoExTra test. We assessed the costs and clinical benefits of test choice. METHODS A Microsoft Excel-based model was developed to evaluate test choice in patients with advanced/metastatic non-small cell lung cancer (NSCLC), breast, prostate, and colorectal cancer. Treatment pathways were based on NCCN guidelines and medical expert opinion. Inputs were derived from published literature. Annual economic results and lifetime clinical results with OncoExTra testing were projected per-tested-patient and compared with single gene testing and no testing. Separately, results were estimated for a US health plan without the OncoExTra test and with its use in 5% of patients. RESULTS Compared with no genomic testing, OncoExTra test use increased costs by $4,915 per patient; however, 82%-92% of individuals across tumour types were identified as eligible for targeted therapy or a clinical trial. Compared with single gene testing, OncoExTra test use decreased costs by $9,966 per-patient-tested while increasing use of approved or investigational targeted therapies by 20%. When considering a hypothetical health plan with 1 million members, 858 patients were eligible for genomic testing. Using the OncoExTra test in 5% of those eligible, per-member per-month costs decreased by $0.003, ranging from cost-savings of $0.026 in NSCLC patients to a $0.009 increase in prostate cancer patients. Cost-savings were driven by reduced treatment costs with increased clinical trial enrolment and reduced direct and indirect medical costs associated with targeted treatments. LIMITATIONS Limitations include the required simplifications in modelling complex conditions that may not fully reflect evolving real-world testing and treatment patterns. CONCLUSIONS Compared to single-gene testing, results indicate that using next generation sequencing test such as OncoExTra identified more actionable alterations, leading to improved outcomes and reduced costs.
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Affiliation(s)
- Jesse D Ortendahl
- Partnership for Health Analytic Research (PHAR), LLC, Beverly Hills, CA, USA
| | | | | | - Katalin Bognar
- Partnership for Health Analytic Research (PHAR), LLC, Beverly Hills, CA, USA
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Wang D, Wang S, Zhang Y, Cheng X, Huang X, Han Y, Chen Z, Liu C, Li J, Zhang R. Validation and benchmarking of targeted panel sequencing for cancer genomic profiling. Am J Clin Pathol 2023; 160:507-523. [PMID: 37477357 DOI: 10.1093/ajcp/aqad078] [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: 03/28/2023] [Accepted: 06/22/2023] [Indexed: 07/22/2023] Open
Abstract
OBJECTIVES To validate a large next-generation sequencing (NGS) panel for comprehensive genomic profiling and improve patient access to more effective precision oncology treatment strategies. METHODS OncoPanScan was designed by targeting 825 cancer-related genes to detect a broad range of genomic alterations. A practical validation strategy was used to evaluate the assay's analytical performance, involving 97 tumor specimens with 25 paired blood specimens, 10 engineered cell lines, and 121 artificial reference DNA samples. RESULTS Overall, 1107 libraries were prepared and the sequencing failure rate was 0.18%. Across alteration classes, sensitivity ranged from 0.938 to more than 0.999, specificity ranged from 0.889 to more than 0.999, positive predictive value ranged from 0.867 to more than 0.999, repeatability ranged from 0.908 to more than 0.999, and reproducibility ranged from 0.832 to more than 0.999. The limit of detection for variants was established based on variant frequency, while for tumor mutation burden and microsatellite instability, it was based on tumor content, resulting in a minimum requirement of 20% tumor content. Benchmarking variant calls against validated NGS assays revealed that variations in the dry-bench processes were the primary cause of discordances. CONCLUSIONS This study presents a detailed validation framework and empirical recommendations for large panel validation and elucidates the sources of discordant alteration calls by comparing with "gold standard measures."
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Affiliation(s)
- Duo Wang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | | | - Yuanfeng Zhang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | | | - Xin Huang
- Genetron Health (Beijing), Beijing, China
| | - Yanxi Han
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | | | - Cong Liu
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Jinming Li
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
| | - Rui Zhang
- National Center for Clinical Laboratories, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences, Beijing Hospital/National Center of Gerontology, Beijing, China
- National Center for Clinical Laboratories, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
- Beijing Engineering Research Center of Laboratory Medicine, Beijing Hospital, Beijing, China
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12
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Grypari IM, Tzelepi V, Gyftopoulos K. DNA Damage Repair Pathways in Prostate Cancer: A Narrative Review of Molecular Mechanisms, Emerging Biomarkers and Therapeutic Targets in Precision Oncology. Int J Mol Sci 2023; 24:11418. [PMID: 37511177 PMCID: PMC10380086 DOI: 10.3390/ijms241411418] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2023] [Revised: 07/09/2023] [Accepted: 07/11/2023] [Indexed: 07/30/2023] Open
Abstract
Prostate cancer (PCa) has a distinct molecular signature, including characteristic chromosomal translocations, gene deletions and defective DNA damage repair mechanisms. One crucial pathway involved is homologous recombination deficiency (HRD) and it is found in almost 20% of metastatic castrate-resistant PCa (mCRPC). Inherited/germline mutations are associated with a hereditary predisposition to early PCa development and aggressive behavior. BRCA2, ATM and CHECK2 are the most frequently HRD-mutated genes. BRCA2-mutated tumors have unfavorable clinical and pathological characteristics, such as intraductal carcinoma. PARP inhibitors, due to the induction of synthetic lethality, have been therapeutically approved for mCRPC with HRD alterations. Mutations are detected in metastatic tissue, while a liquid biopsy is utilized during follow-up, recognizing acquired resistance mechanisms. The mismatch repair (MMR) pathway is another DNA repair mechanism implicated in carcinogenesis, although only 5% of metastatic PCa is affected. It is associated with aggressive disease. PD-1 inhibitors have been used in MMR-deficient tumors; thus, the MMR status should be tested in all metastatic PCa cases. A surrogate marker of defective DNA repair mechanisms is the tumor mutational burden. PDL-1 expression and intratumoral lymphocytes have ambivalent predictive value. Few experimental molecules have been so far proposed as potential biomarkers. Future research may further elucidate the role of DNA damage pathways in PCa, revealing new therapeutic targets and predictive biomarkers.
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Affiliation(s)
- Ioanna-Maria Grypari
- Cytology Department, Aretaieion University Hospital, National Kapodistrian University of Athens, 11528 Athens, Greece
| | - Vasiliki Tzelepi
- Department of Pathology, School of Medicine, University of Patras, 26504 Patras, Greece
| | - Kostis Gyftopoulos
- Department of Anatomy, School of Medicine, University of Patras, 26504 Patras, Greece
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13
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Şenocak Taşçı E, Yıldız İ, Erdamar S, Özer L. Discrepancy among microsatellite instability detection methodologies in non-colorectal cancer: Report of 3 cases. World J Clin Cases 2023; 11:3105-3113. [PMID: 37215411 PMCID: PMC10198076 DOI: 10.12998/wjcc.v11.i13.3105] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/07/2023] [Revised: 03/16/2023] [Accepted: 04/04/2023] [Indexed: 04/25/2023] Open
Abstract
BACKGROUND Microsatellite instability (MSI) is a predictive biomarker for cancer immunotherapy. The tumor-agnostic nature of MSI makes it a denominator for immunotherapy in several solid tumors. It can be assessed using next-generation sequencing (NGS), fluorescent multiplex PCR, and immunohistochemistry (IHC). CASE SUMMARY Here, we report 3 cases with discordant MSI results detected using different methods. A cholangiocellular carcinoma case revealed proficient mismatch repair (MMR) by IHC but high MSI (MSI-H) by liquid NGS. A cervical cancer case revealed deficient MMR by IHC, microsatellite stable by PCR, and MSI-H by NGS. Lastly, an endometrial cancer case revealed proficient MMR by IHC but MSI-H by NGS. CONCLUSION IHC for MMR status is the first choice due to several advantages. However, in cases of indeterminate IHC results, molecular testing by MSI-PCR is preferred. Recently, NGS-based MSI assays are being widely used to detect MSI-H tumors. All three methods have high accuracy; however, the inconsistencies between them may lead to misdiagnosis.
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Affiliation(s)
- Elif Şenocak Taşçı
- Department of Medical Oncology, Acıbadem MAA University, Istanbul 12345, Turkey
| | - İbrahim Yıldız
- Department of Medical Oncology, Acıbadem MAA University, Istanbul 12345, Turkey
| | - Sibel Erdamar
- Department of Pathology, Acıbadem MAA University, Istanbul 12345, Turkey
| | - Leyla Özer
- Department of Medical Oncology, Acıbadem MAA University, Istanbul 12345, Turkey
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14
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Nourmohammadi Abadchi S, Sena LA, Antonarakis ES, Pritchard CC, Eshleman JR, Konnick EQ, Salipante SJ, Shenderov E, Lotan TL. MLH1 Loss in Primary Prostate Cancer. JCO Precis Oncol 2023; 7:e2200611. [PMID: 37196219 PMCID: PMC10309570 DOI: 10.1200/po.22.00611] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2022] [Revised: 01/25/2023] [Accepted: 03/17/2023] [Indexed: 05/19/2023] Open
Abstract
PURPOSE Among mismatch repair-deficient (MMRd) prostate cancers, loss of MLH1 is relatively uncommon and few cases have been reported in detail. METHODS Here, we describe the molecular features of two cases of primary prostate cancer with MLH1 loss detected by immunohistochemistry, and in one case, confirmed via transcriptomic profiling. RESULTS Both cases were microsatellite stable on standard polymerase chain reaction (PCR)-based microsatellite instability (MSI) testing, but showed evidence of MSI on a newer PCR-based long mononucleotide repeat (LMR) assay and by next-generation sequencing. Germline testing was negative for Lynch syndrome-associated mutations in both cases. Targeted or whole-exome tumor sequencing using multiple commercial/academic platforms (Foundation, Tempus, JHU, and UW-OncoPlex) showed modestly elevated, though variable, tumor mutation burden estimates (2.3-10 mutations/Mb) consistent with MMRd, but without identifiable pathogenic single-nucleotide or indel mutations in MLH1. Copy-number analysis confirmed biallelic MLH1 loss in one case and monoallelic MLH1 loss in the second case, without evidence of MLH1 promoter hypermethylation in either. The second patient was treated with single-agent pembrolizumab and demonstrated a short-lived prostate-specific antigen response. CONCLUSION These cases highlight the challenges in identifying MLH1-deficient prostate cancers using standard MSI testing and commercial sequencing panels, and support the utility of immunohistochemical assays and LMR- or sequencing-based MSI testing for detection of MMRd prostate cancers.
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Affiliation(s)
| | - Laura A. Sena
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD
| | - Emmanuel S. Antonarakis
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD
- University of Minnesota Masonic Cancer Center, Minneapolis, MN
| | - Colin C. Pritchard
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA
| | - James R. Eshleman
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD
| | - Eric Q. Konnick
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA
| | - Stephen J. Salipante
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, WA
| | - Eugene Shenderov
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD
- The Bloomberg-Kimmel Institute for Cancer Immunotherapy, Johns Hopkins School of Medicine, Baltimore, MD
| | - Tamara L. Lotan
- Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD
- Department of Oncology, Johns Hopkins School of Medicine, Baltimore, MD
- Department of Urology, Johns Hopkins School of Medicine, Baltimore, MD
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15
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Patel L, Pritchard CC. Molecular testing of DNA damage response pathways in prostate cancer patients. Curr Opin Oncol 2023; 35:224-230. [PMID: 36966502 DOI: 10.1097/cco.0000000000000934] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2023]
Abstract
PURPOSE OF REVIEW Personalizing prostate cancer therapy requires germline and tumor molecular tests that predict who will respond to specific treatments and who may not. The review covers molecular testing of DNA damage response pathways, the first biomarker-driven precision target with clinical utility for treatment selection in patients with castration resistant prostate cancer (CRPC). RECENT FINDINGS Recurrent somatic and germline variants cause deficiency of the mismatch repair (MMR) or homologous recombination (HR) pathways in about a quarter of CRPC patients. In prospective clinical trials, patients with deleterious variants in the MMR pathway more frequently experience a therapeutic response to immune checkpoint inhibitors (ICI). Similarly, somatic and germline events affecting HR predict response to poly(ADP) ribose polymerase inhibitor (PARPi) therapy. Molecular testing of these pathways currently involves assaying for loss of function variants in individual genes and for the genome-wide consequences of repair deficiency. SUMMARY DNA damage response pathways are the first major area of molecular genetic testing in CRPC settings and offer insights into this new paradigm. Our hope is that eventually an arsenal of molecularly-guided therapies will be developed across many pathways to enable precision medicine options for most men with prostate cancer.
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Affiliation(s)
- Lalit Patel
- Department of Genetics, The University of Texas MD Anderson Cancer Center, Houston, Texas
| | - Colin C Pritchard
- Department of Laboratory Medicine and Pathology, University of Washington
- Brotman Baty Institute for Precision Medicine, Seattle, Washington, USA
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16
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Gillessen S, Bossi A, Davis ID, de Bono J, Fizazi K, James ND, Mottet N, Shore N, Small E, Smith M, Sweeney CJ, Tombal B, Antonarakis ES, Aparicio AM, Armstrong AJ, Attard G, Beer TM, Beltran H, Bjartell A, Blanchard P, Briganti A, Bristow RG, Bulbul M, Caffo O, Castellano D, Castro E, Cheng HH, Chi KN, Chowdhury S, Clarke CS, Clarke N, Daugaard G, De Santis M, Duran I, Eeles R, Efstathiou E, Efstathiou J, Ekeke ON, Evans CP, Fanti S, Feng FY, Fonteyne V, Fossati N, Frydenberg M, George D, Gleave M, Gravis G, Halabi S, Heinrich D, Herrmann K, Higano C, Hofman MS, Horvath LG, Hussain M, Jereczek-Fossa BA, Jones R, Kanesvaran R, Kellokumpu-Lehtinen PL, Khauli RB, Klotz L, Kramer G, Leibowitz R, Logothetis C, Mahal B, Maluf F, Mateo J, Matheson D, Mehra N, Merseburger A, Morgans AK, Morris MJ, Mrabti H, Mukherji D, Murphy DG, Murthy V, Nguyen PL, Oh WK, Ost P, O'Sullivan JM, Padhani AR, Pezaro CJ, Poon DMC, Pritchard CC, Rabah DM, Rathkopf D, Reiter RE, Rubin MA, Ryan CJ, Saad F, Sade JP, Sartor O, Scher HI, Sharifi N, Skoneczna I, Soule H, Spratt DE, Srinivas S, Sternberg CN, Steuber T, Suzuki H, et alGillessen S, Bossi A, Davis ID, de Bono J, Fizazi K, James ND, Mottet N, Shore N, Small E, Smith M, Sweeney CJ, Tombal B, Antonarakis ES, Aparicio AM, Armstrong AJ, Attard G, Beer TM, Beltran H, Bjartell A, Blanchard P, Briganti A, Bristow RG, Bulbul M, Caffo O, Castellano D, Castro E, Cheng HH, Chi KN, Chowdhury S, Clarke CS, Clarke N, Daugaard G, De Santis M, Duran I, Eeles R, Efstathiou E, Efstathiou J, Ekeke ON, Evans CP, Fanti S, Feng FY, Fonteyne V, Fossati N, Frydenberg M, George D, Gleave M, Gravis G, Halabi S, Heinrich D, Herrmann K, Higano C, Hofman MS, Horvath LG, Hussain M, Jereczek-Fossa BA, Jones R, Kanesvaran R, Kellokumpu-Lehtinen PL, Khauli RB, Klotz L, Kramer G, Leibowitz R, Logothetis C, Mahal B, Maluf F, Mateo J, Matheson D, Mehra N, Merseburger A, Morgans AK, Morris MJ, Mrabti H, Mukherji D, Murphy DG, Murthy V, Nguyen PL, Oh WK, Ost P, O'Sullivan JM, Padhani AR, Pezaro CJ, Poon DMC, Pritchard CC, Rabah DM, Rathkopf D, Reiter RE, Rubin MA, Ryan CJ, Saad F, Sade JP, Sartor O, Scher HI, Sharifi N, Skoneczna I, Soule H, Spratt DE, Srinivas S, Sternberg CN, Steuber T, Suzuki H, Sydes MR, Taplin ME, Tilki D, Türkeri L, Turco F, Uemura H, Uemura H, Ürün Y, Vale CL, van Oort I, Vapiwala N, Walz J, Yamoah K, Ye D, Yu EY, Zapatero A, Zilli T, Omlin A. Management of patients with advanced prostate cancer-metastatic and/or castration-resistant prostate cancer: Report of the Advanced Prostate Cancer Consensus Conference (APCCC) 2022. Eur J Cancer 2023; 185:178-215. [PMID: 37003085 DOI: 10.1016/j.ejca.2023.02.018] [Show More Authors] [Citation(s) in RCA: 87] [Impact Index Per Article: 43.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/17/2023] [Accepted: 02/22/2023] [Indexed: 03/06/2023]
Abstract
BACKGROUND Innovations in imaging and molecular characterisation together with novel treatment options have improved outcomes in advanced prostate cancer. However, we still lack high-level evidence in many areas relevant to making management decisions in daily clinical practise. The 2022 Advanced Prostate Cancer Consensus Conference (APCCC 2022) addressed some questions in these areas to supplement guidelines that mostly are based on level 1 evidence. OBJECTIVE To present the voting results of the APCCC 2022. DESIGN, SETTING, AND PARTICIPANTS The experts voted on controversial questions where high-level evidence is mostly lacking: locally advanced prostate cancer; biochemical recurrence after local treatment; metastatic hormone-sensitive, non-metastatic, and metastatic castration-resistant prostate cancer; oligometastatic prostate cancer; and managing side effects of hormonal therapy. A panel of 105 international prostate cancer experts voted on the consensus questions. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS The panel voted on 198 pre-defined questions, which were developed by 117 voting and non-voting panel members prior to the conference following a modified Delphi process. A total of 116 questions on metastatic and/or castration-resistant prostate cancer are discussed in this manuscript. In 2022, the voting was done by a web-based survey because of COVID-19 restrictions. RESULTS AND LIMITATIONS The voting reflects the expert opinion of these panellists and did not incorporate a standard literature review or formal meta-analysis. The answer options for the consensus questions received varying degrees of support from panellists, as reflected in this article and the detailed voting results are reported in the supplementary material. We report here on topics in metastatic, hormone-sensitive prostate cancer (mHSPC), non-metastatic, castration-resistant prostate cancer (nmCRPC), metastatic castration-resistant prostate cancer (mCRPC), and oligometastatic and oligoprogressive prostate cancer. CONCLUSIONS These voting results in four specific areas from a panel of experts in advanced prostate cancer can help clinicians and patients navigate controversial areas of management for which high-level evidence is scant or conflicting and can help research funders and policy makers identify information gaps and consider what areas to explore further. However, diagnostic and treatment decisions always have to be individualised based on patient characteristics, including the extent and location of disease, prior treatment(s), co-morbidities, patient preferences, and treatment recommendations and should also incorporate current and emerging clinical evidence and logistic and economic factors. Enrolment in clinical trials is strongly encouraged. Importantly, APCCC 2022 once again identified important gaps where there is non-consensus and that merit evaluation in specifically designed trials. PATIENT SUMMARY The Advanced Prostate Cancer Consensus Conference (APCCC) provides a forum to discuss and debate current diagnostic and treatment options for patients with advanced prostate cancer. The conference aims to share the knowledge of international experts in prostate cancer with healthcare providers worldwide. At each APCCC, an expert panel votes on pre-defined questions that target the most clinically relevant areas of advanced prostate cancer treatment for which there are gaps in knowledge. The results of the voting provide a practical guide to help clinicians discuss therapeutic options with patients and their relatives as part of shared and multidisciplinary decision-making. This report focuses on the advanced setting, covering metastatic hormone-sensitive prostate cancer and both non-metastatic and metastatic castration-resistant prostate cancer. TWITTER SUMMARY Report of the results of APCCC 2022 for the following topics: mHSPC, nmCRPC, mCRPC, and oligometastatic prostate cancer. TAKE-HOME MESSAGE At APCCC 2022, clinically important questions in the management of advanced prostate cancer management were identified and discussed, and experts voted on pre-defined consensus questions. The report of the results for metastatic and/or castration-resistant prostate cancer is summarised here.
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Affiliation(s)
- Silke Gillessen
- Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland; Università della Svizzera Italiana, Lugano, Switzerland.
| | - Alberto Bossi
- Genitourinary Oncology, Prostate Brachytherapy Unit, Gustave Roussy, Paris, France
| | - Ian D Davis
- Monash University and Eastern Health, Victoria, Australia
| | - Johann de Bono
- The Institute of Cancer Research, London, UK; Royal Marsden Hospital, London, UK
| | - Karim Fizazi
- Institut Gustave Roussy, University of Paris Saclay, Villejuif, France
| | | | | | - Neal Shore
- Medical Director, Carolina Urologic Research Center, Myrtle Beach, SC, USA; CMO, Urology/Surgical Oncology, GenesisCare, Myrtle Beach, SC, USA
| | - Eric Small
- UCSF Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA
| | - Matthew Smith
- Massachusetts General Hospital Cancer Center, Boston, MA, USA
| | - Christopher J Sweeney
- South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, Australia
| | | | | | - Ana M Aparicio
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Andrew J Armstrong
- Duke Cancer Institute Center for Prostate and Urologic Cancers, Durham, NC, USA
| | | | - Tomasz M Beer
- Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA
| | - Himisha Beltran
- Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Anders Bjartell
- Department of Urology, Skåne University Hospital, Malmö, Sweden
| | - Pierre Blanchard
- Gustave Roussy, Département de Radiothérapie, Université Paris-Saclay, Oncostat, Inserm U-1018, F-94805, Villejuif, France
| | - Alberto Briganti
- Unit of Urology/Division of Oncology, URI, IRCCS Ospedale San Raffaele, Vita-Salute San Raffaele University, Milan, Italy
| | - Rob G Bristow
- Division of Cancer Sciences, Faculty of Biology, Medicine and Health, University of Manchester, Manchester, UK; Christie NHS Trust and CRUK Manchester Institute and Cancer Centre, Manchester, UK
| | - Muhammad Bulbul
- Division of Urology, Department of Surgery, American University of Beirut Medical Center, Beirut, Lebanon
| | - Orazio Caffo
- Department of Medical Oncology, Santa Chiara Hospital, 38122 Trento, Italy
| | - Daniel Castellano
- Medical Oncology, Hospital Universitario 12 de Octubre, Madrid, Spain
| | - Elena Castro
- Institute of Biomedical Research in Málaga (IBIMA), Málaga, Spain
| | - Heather H Cheng
- University of Washington, Fred Hutchinson Cancer Center, Seattle, WA, USA
| | - Kim N Chi
- BC Cancer, Vancouver Prostate Centre, University of British Columbia, Vancouver, British Columbia, Canada
| | - Simon Chowdhury
- Guys and St Thomas's NHS Foundation Trust, London, United Kingdom
| | - Caroline S Clarke
- Research Department of Primary Care & Population Health, Royal Free Campus, University College London, London, UK
| | - Noel Clarke
- The Christie and Salford Royal Hospitals, Manchester, UK
| | - Gedske Daugaard
- Department of Oncology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark
| | - Maria De Santis
- Department of Urology, Charité Universitätsmedizin, Berlin, Germany; Department of Urology, Medical University of Vienna, Austria
| | - Ignacio Duran
- Department of Medical Oncology, Hospital Universitario Marques de Valdecilla, IDIVAL, Santander, Cantabria, Spain
| | - Ross Eeles
- The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, London, UK
| | | | - Jason Efstathiou
- Department of Radiation Oncology, Massachusetts General Hospital, Boston, MA, USA
| | - Onyeanunam Ngozi Ekeke
- Department of Surgery, University of Port Harcourt Teaching Hospital, Alakahia, Port Harcourt, Nigeria
| | | | - Stefano Fanti
- IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy
| | - Felix Y Feng
- University of California, San Francisco, San Francisco, CA, USA
| | - Valerie Fonteyne
- Department of Radiation-Oncology, Ghent University Hospital, Ghent, Belgium
| | - Nicola Fossati
- Department of Urology, Ospedale Regionale di Lugano, Civico USI - Università della Svizzera Italiana, Lugano, Switzerland
| | - Mark Frydenberg
- Department of Surgery, Prostate Cancer Research Program, Department of Anatomy & Developmental Biology, Faculty Nursing, Medicine & Health Sciences, Monash University, Melbourne, Australia
| | - Dan George
- Departments of Medicine and Surgery, Duke Cancer Institute, Duke University, Durham, NC, USA
| | - Martin Gleave
- Urological Sciences, Vancouver Prostate Centre, University of British Columbia, Vancouver, Canada
| | - Gwenaelle Gravis
- Department of Medical Oncology, Institut Paoli Calmettes, Aix-Marseille Université, Marseille, France
| | - Susan Halabi
- Department of Biostatistics and Bioinformatics, Duke University, Durham, NC, USA
| | - Daniel Heinrich
- Department of Oncology and Radiotherapy, Innlandet Hospital Trust, Gjøvik, Norway
| | - Ken Herrmann
- Department of Nuclear Medicine, University of Duisburg-Essen and German Cancer Consortium (DKTK)-University Hospital Essen, Essen, Germany
| | - Celestia Higano
- University of British Columbia, Vancouver, British Columbia, Canada
| | - Michael S Hofman
- Prostate Cancer Theranostics and Imaging Centre of Excellence, Department of Molecular Imaging and Therapeutic Nuclear Medicine, Peter MacCallum Cancer Centre and Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Australia
| | - Lisa G Horvath
- Chris O'Brien Lifehouse, Camperdown, NSW, Australia; Garvan Institute of Medical Research, Darlinghurst, Sydney, NSW, Australia; The University of Sydney, Sydney, NSW, Australia
| | - Maha Hussain
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Barbara A Jereczek-Fossa
- Department of Oncology and Hemato-Oncology, University of Milan, Milan, Italy; Department of Radiotherapy, European Institute of Oncology (IEO) IRCCS, Milan, Italy
| | - Rob Jones
- School of Cancer Sciences, University of Glasgow, United Kingdom
| | | | - Pirkko-Liisa Kellokumpu-Lehtinen
- Faculty of Medicine and Health Technology, Tampere University and Tampere Cancer Center, Tampere, Finland; Research, Development and Innovation Center, Tampere University Hospital, Tampere, Finland
| | - Raja B Khauli
- Division of Urology and the Naef K. Basile Cancer Institute (NKBCI), American University of Beirut Medical Center, Beirut, Lebanon
| | - Laurence Klotz
- Division of Urology, Sunnybrook Health Sciences Centre, University of Toronto, Toronto, ON, Canada
| | - Gero Kramer
- Department of Urology, Medical University of Vienna, Vienna, Austria
| | - Raja Leibowitz
- Oncology Institute, Shamir Medical Center, Be'er Ya'akov, Israel; Faculty of Medicine, Tel-Aviv University, Israel
| | - Christopher Logothetis
- Department of Genitourinary Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; University of Athens Alexandra Hospital, Athens, Greece
| | - Brandon Mahal
- Department of Radiation Oncology, University of Miami Sylvester Cancer Center, Miami, FL, USA
| | - Fernando Maluf
- Beneficiência Portuguesa de São Paulo, São Paulo, SP, Brasil; Departamento de Oncologia, Hospital Israelita Albert Einstein, São Paulo, SP, Brazil
| | - Joaquin Mateo
- Department of Medical Oncology and Prostate Cancer Translational Research Group. Vall d'Hebron Institute of Oncology (VHIO) and Vall d'Hebron University Hospital, Barcelona, Spain
| | - David Matheson
- Faculty of Education, Health and Wellbeing, Walsall Campus, Walsall, UK
| | - Niven Mehra
- Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Axel Merseburger
- Department of Urology, University Hospital Schleswig-Holstein, Luebeck, Germany
| | - Alicia K Morgans
- Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Michael J Morris
- Genitourinary Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Hind Mrabti
- National Institute of Oncology, Mohamed V University, Rabat, Morocco
| | - Deborah Mukherji
- Clemenceau Medical Center Dubai, United Arab Emirates, Faculty of Medicine, American University of Beirut, Lebanon
| | - Declan G Murphy
- Division of Cancer Surgery, Peter MacCallum Cancer Centre, Melbourne, Australia; Sir Peter MacCallum Department of Oncology, University of Melbourne, Parkville, Australia
| | | | - Paul L Nguyen
- Department of Radiation Oncology, Brigham and Women's Hospital and Dana Farber Cancer Institute, Harvard Medical School, Boston, MA, USA
| | - William K Oh
- Chief, Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, The Tisch Cancer Institute, New York, NY, USA
| | - Piet Ost
- Department of Human Structure and Repair, Ghent University, Ghent, Belgium; Department of Radiation Oncology, Iridium Netwerk, Antwerp, Belgium, Ghent University, Ghent, Belgium
| | - Joe M O'Sullivan
- Patrick G. Johnston Centre for Cancer Research, Queen's University Belfast, Northern Ireland Cancer Centre, Belfast City Hospital, Belfast, Northern Ireland
| | - Anwar R Padhani
- Mount Vernon Cancer Centre and Institute of Cancer Research, London, UK
| | - Carmel J Pezaro
- Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | - Darren M C Poon
- Comprehensive Oncology Centre, Hong Kong Sanatorium & Hospital, Hong Kong; The Chinese University of Hong Kong, Shatin, Hong Kong
| | - Colin C Pritchard
- Department of Laboratory Medicine and Pathology, University of Washington, Seattle, USA
| | - Danny M Rabah
- Cancer Research Chair and Department of Surgery, College of Medicine, King Saud University, Riyadh, Saudi Arabia; Department of Urology, KFSHRC Riyadh, Saudi Arabia
| | - Dana Rathkopf
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | | | - Mark A Rubin
- Bern Center for Precision Medicine and Department for Biomedical Research, Bern, Switzerland
| | - Charles J Ryan
- Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA
| | - Fred Saad
- Centre Hospitalier de Université de Montréal, Montreal, Canada
| | | | | | - Howard I Scher
- Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA; Department of Medicine, Weill Cornell Medical College, New York, NY, USA
| | - Nima Sharifi
- Department of Hematology and Oncology, Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, USA; Department of Cancer Biology, GU Malignancies Research Center, Cleveland Clinic Lerner Research Institute, Cleveland, OH, USA
| | - Iwona Skoneczna
- Rafal Masztak Grochowski Hospital, Maria Sklodowska Curie National Research Institute of Oncology, Warsaw, Poland
| | - Howard Soule
- Prostate Cancer Foundation, Santa Monica, CA, USA
| | - Daniel E Spratt
- University Hospitals Seidman Cancer Center, Cleveland, OH, USA
| | - Sandy Srinivas
- Division of Medical Oncology, Stanford University Medical Center, Stanford, CA, USA
| | - Cora N Sternberg
- Englander Institute for Precision Medicine, Weill Cornell Medicine, Division of Hematology and Oncology, Meyer Cancer Center, New York Presbyterian Hospital, New York, NY, USA
| | - Thomas Steuber
- Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | | | - Matthew R Sydes
- MRC Clinical Trials Unit at UCL, Institute of Clinical Trials and Methodology, University College London, London, UK
| | - Mary-Ellen Taplin
- Department of Medical Oncology, Dana-Farber Cancer Institute and Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Derya Tilki
- Martini-Klinik Prostate Cancer Center, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Urology, University Hospital Hamburg-Eppendorf, Hamburg, Germany; Department of Urology, Koc University Hospital, Istanbul, Turkey
| | - Levent Türkeri
- Department of Urology, M.A. Aydınlar Acıbadem University, Altunizade Hospital, Istanbul, Turkey
| | - Fabio Turco
- Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland
| | - Hiroji Uemura
- Yokohama City University Medical Center, Yokohama, Japan
| | - Hirotsugu Uemura
- Department of Urology, Kindai University Faculty of Medicine, Osaka, Japan
| | - Yüksel Ürün
- Department of Medical Oncology, Ankara University School of Medicine, Ankara, Turkey; Ankara University Cancer Research Institute, Ankara, Turkey
| | - Claire L Vale
- University College London, MRC Clinical Trials Unit at UCL, London, UK
| | - Inge van Oort
- Department of Urology, Radboud University Medical Center, Nijmegen, the Netherlands
| | - Neha Vapiwala
- Department of Radiation Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, PA, USA
| | - Jochen Walz
- Department of Urology, Institut Paoli-Calmettes Cancer Centre, Marseille, France
| | - Kosj Yamoah
- Department of Radiation Oncology & Cancer Epidemiology, H. Lee Moffitt Cancer Center & Research Institute, University of South Florida, Tampa, FL, USA
| | - Dingwei Ye
- Department of Urology, Fudan University Shanghai Cancer Center, Shanghai, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Evan Y Yu
- Department of Medicine, Division of Oncology, University of Washington and Fred Hutchinson Cancer Center, G4-830, Seattle, WA, USA
| | - Almudena Zapatero
- Department of Radiation Oncology, Hospital Universitario de La Princesa, Health Research Institute, Madrid, Spain
| | - Thomas Zilli
- Radiation Oncology, Oncology Institute of Southern Switzerland, EOC, Bellinzona, Switzerland; Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | - Aurelius Omlin
- Onkozentrum Zurich, University of Zurich and Tumorzentrum Hirslanden Zurich, Switzerland
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Rasmussen M, Sowter P, Gallon R, Durhuus JA, Hayes C, Andersen O, Nilbert M, Schejbel L, Høgdall E, Santibanez-Koref M, Jackson MS, Burn J, Therkildsen C. Mismatch repair deficiency testing in Lynch syndrome-associated urothelial tumors. Front Oncol 2023; 13:1147591. [PMID: 37143941 PMCID: PMC10151563 DOI: 10.3389/fonc.2023.1147591] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2023] [Accepted: 03/23/2023] [Indexed: 05/06/2023] Open
Abstract
Introduction Lynch syndrome-associated cancer develops due to germline pathogenic variants in one of the mismatch repair (MMR) genes, MLH1, MSH2, MSH6 or PMS2. Somatic second hits in tumors cause MMR deficiency, testing for which is used to screen for Lynch syndrome in colorectal cancer and to guide selection for immunotherapy. Both MMR protein immunohistochemistry and microsatellite instability (MSI) analysis can be used. However, concordance between methods can vary for different tumor types. Therefore, we aimed to compare methods of MMR deficiency testing in Lynch syndrome-associated urothelial cancers. Methods Ninety-seven urothelial (61 upper tract and 28 bladder) tumors diagnosed from 1980 to 2017 in carriers of Lynch syndrome-associated pathogenic MMR variants and their first-degree relatives (FDR) were analyzed by MMR protein immunohistochemistry, the MSI Analysis System v1.2 (Promega), and an amplicon sequencing-based MSI assay. Two sets of MSI markers were used in sequencing-based MSI analysis: a panel of 24 and 54 markers developed for colorectal cancer and blood MSI analysis, respectively. Results Among the 97 urothelial tumors, 86 (88.7%) showed immunohistochemical MMR loss and 68 were successfully analyzed by the Promega MSI assay, of which 48 (70.6%) were MSI-high and 20 (29.4%) were MSI-low/microsatellite stable. Seventy-two samples had sufficient DNA for the sequencing-based MSI assay, of which 55 (76.4%) and 61 (84.7%) scored as MSI-high using the 24-marker and 54-marker panels, respectively. The concordance between the MSI assays and immunohistochemistry was 70.6% (p = 0.003), 87.5% (p = 0.039), and 90.3% (p = 1.00) for the Promega assay, the 24-marker assay, and the 54-marker assay, respectively. Of the 11 tumors with retained MMR protein expression, four were MSI-low/MSI-high or MSI-high by the Promega assay or one of the sequencing-based assays. Conclusion Our results show that Lynch syndrome-associated urothelial cancers frequently had loss of MMR protein expression. The Promega MSI assay was significantly less sensitive, but the 54-marker sequencing-based MSI analysis showed no significant difference compared to immunohistochemistry. Data from this study alongside previous studies, suggest that universal MMR deficiency testing of newly diagnosed urothelial cancers, using immunohistochemistry and/or sequencing-based MSI analysis of sensitive markers, offer a potentially useful approach to identification of Lynch syndrome cases.
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Affiliation(s)
- Maria Rasmussen
- Department of Clinical Research, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark
| | - Peter Sowter
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Richard Gallon
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Jon Ambæk Durhuus
- Department of Clinical Research, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark
- Center for Healthy Aging, Department of Cellular and Molecular Medicine, University of Copenhagen, Copenhagen, Denmark
| | - Christine Hayes
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Ove Andersen
- Department of Clinical Research, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark
| | - Mef Nilbert
- Institute of Clinical Sciences, Division of Oncology and Pathology, Lund University, Lund, Sweden
| | - Lone Schejbel
- Molecular Unit, Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Estrid Høgdall
- Molecular Unit, Department of Pathology, Copenhagen University Hospital - Herlev and Gentofte, Copenhagen, Denmark
| | - Mauro Santibanez-Koref
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Michael S Jackson
- Biosciences Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - John Burn
- Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, United Kingdom
| | - Christina Therkildsen
- The Danish HNPCC Register, Gastro Unit, Copenhagen University Hospital - Amager and Hvidovre, Copenhagen, Denmark
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He L, Yang J, Zhang B, Wang Y, Wang J, Ye Q. A comparison of performance of 6-mononucleotide site panel and NCI panel for microsatellite instability detection in patients with colorectal adenocarcinoma. Pathol Res Pract 2023; 244:154390. [PMID: 36905693 DOI: 10.1016/j.prp.2023.154390] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2022] [Revised: 01/17/2023] [Accepted: 02/26/2023] [Indexed: 03/02/2023]
Abstract
BACKGROUND Microsatellite instability (MSI) represents as a molecular hallmark of deficient MMR system at the genomic level. Increasing clinical significance of MSI status highlights the necessity of simple, accurate markers for detection. Although 2B3D NCI panel is the most widely applied, it has been questioned whether the performance of NCI panel is second to none in MSI detection. METHODS We evaluated the efficacy of the NCI panel versus a 6-mononucleotide site panel (BAT25, BAT26, NR21, NR24, NR27, and MONO-27) in assessing MSI status of 468 Chinese patients with CRC, and compared MSI test results with the results by immunohistochemistry of four MMR proteins (MLH1, PMS2, MSH2, MSH6) in the present study. Clinicopathological variables were also collected, and their associations with MSI or MMR proteins status were analyzed using either the chi-square test or the Fisher's exact test. RESULTS MSI-H/dMMR was significantly associated with right colon involvement, poor differentiation, early stage, mucinous adenocarcinoma, negative lymph node, less neural invasion, and KRAS/NRAS/BRAF wild-type. As to the efficiency of detecting deficient MMR system, both panels had good concordance with MMR proteins expression by IHC, and 6-mononucleotide site panel outperformed NCI panel in sensitivity, specificity, positive predictive value, and negative predictive value numerically despite the lack of statistical significance. The advantage was more obvious in the sensitivity and specificity analyses of each single microsatellite markers from 6-mononucleotide site panel in comparison with NCI panel. Additionally, the rate of MSI-L detected by 6-mononucleotide site panel was much lower than that detected by the NCI panel (0.64% vs. 2.86%, P = 0.0326). CONCLUSION 6-mononucleotide site panel had a greater ability to help resolve cases of MSI-L into either MSI-H or MSS. We propose that 6-mononucleotide site panel may be potentially more suitable than NCI panel for Chinese CRC population. Large-scale studies are warranted to validate our findings.
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Affiliation(s)
- Lu He
- Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China
| | - Jun Yang
- Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China
| | - Biao Zhang
- Department of Pathology, Nanjing Drum Tower Hospital, the Affiliated Hospital of Nanjing University Medical School, 321 Zhongshan Road, Nanjing 210008, China
| | - Yuyang Wang
- Department of Pathology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Jing Wang
- Department of Pathology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China
| | - Qing Ye
- Department of Pathology, the First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China; Intelligent Pathology Institute, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, China.
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Shinozaki-Ushiku A, Kunita A, Iwasaki A, Kato M, Yamazawa S, Abe H, Ushiku T. Microsatellite instability profiles of gastrointestinal cancers: comparison between non-colorectal and colorectal origin. Histopathology 2023; 82:466-477. [PMID: 36254632 DOI: 10.1111/his.14830] [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: 08/11/2022] [Revised: 09/20/2022] [Accepted: 10/14/2022] [Indexed: 01/20/2023]
Abstract
Microsatellite instability (MSI) is a major carcinogenic pathway with prognostic and predictive implications. The validity of polymerase chain reaction (PCR)-based MSI testing is well established in colorectal cancer; however, the data are limited in non-colorectal gastrointestinal cancers. The aim of this study is to clarify the detailed MSI profiles of non-colorectal gastrointestinal cancers and to investigate the differences from those of colorectal cancers. MSI testing was performed using paired tumour/normal tissues of 123 mismatch repair-deficient cancers detected by immunohistochemistry including 80 non-colorectal cancers (eight oesophagogastric junction (EGJ), 57 gastric and 15 small intestine) and 43 colorectal cancers. Fragment size analysis revealed that the mean nucleotide shifts of five markers (Promega panel) were the highest in the stomach (6.4), followed by colorectum (5.7), small intestine (5.0) and EGJ cancers (mean = 4.0; P = 0.015, versus stomach). All cases showed ≥ 1 nucleotide shift in ≥ 2 markers and were considered as MSI-high. However, when the cut-off was set to ≥ 3 nucleotide shifts in ≥ 2 markers, three EGJ (37.5%), two small intestine (13.3%) and two gastric (3.5%) cancers showed false-negative results. In addition, cases with isolated loss of MSH6 or PMS2 showed smaller nucleotide shifts than those in others. MSI testing is applicable to non-colorectal gastrointestinal cancers; however, a subset can yield false-negative results due to subtle nucleotide shift in multiple markers. Analysis of paired tumour/normal tissues and careful interpretation is necessary to avoid false-negative results and ensure appropriate treatment.
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Affiliation(s)
- Aya Shinozaki-Ushiku
- Department of Pathology, The University of Tokyo, Tokyo, Japan.,Division of Integrative Genomics, The University of Tokyo, Tokyo, Japan
| | - Akiko Kunita
- Department of Pathology, The University of Tokyo, Tokyo, Japan.,Next-Generation Precision Medicine Development Laboratory, The University of Tokyo, Tokyo, Japan
| | - Akiko Iwasaki
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Moe Kato
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Sho Yamazawa
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Abe
- Department of Pathology, The University of Tokyo, Tokyo, Japan
| | - Tetsuo Ushiku
- Department of Pathology, The University of Tokyo, Tokyo, Japan
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Catalano M, Generali D, Gatti M, Riboli B, Paganini L, Nesi G, Roviello G. DNA repair deficiency as circulating biomarker in prostate cancer. Front Oncol 2023; 13:1115241. [PMID: 36793600 PMCID: PMC9922904 DOI: 10.3389/fonc.2023.1115241] [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: 12/03/2022] [Accepted: 01/12/2023] [Indexed: 01/31/2023] Open
Abstract
Deleterious aberrations in DNA repair genes are actionable in approximately 25% of metastatic castration-resistant prostate cancers (mCRPC) patients. Homology recombination repair (HRR) is the DNA damage repair (DDR) mechanism most frequently altered in prostate cancer; of note BRCA2 is the most frequently altered DDR gene in this tumor. Poly ADP-ribose polymerase inhibitors showed antitumor activity with a improvement in overall survival in mCRPC carrying somatic and/or germline alterations of HHR. Germline mutations are tested on peripheral blood samples using DNA extracted from peripheral blood leukocytes, while the somatic alterations are assessed by extracting DNA from a tumor tissue sample. However, each of these genetic tests have some limitations: the somatic tests are related to the sample availability and tumor heterogeneity, while the germline testing are mainly related to the inability to detect somatic HRR mutations. Therefore, the liquid biopsy, a non-invasive and easily repeatable test compared to tissue test, could identified somatic mutation detected on the circulating tumor DNA (ctDNA) extracted from a plasma. This approach should better represent the heterogeneity of the tumor compared to the primary biopsy and maybe helpful in monitoring the onset of potential mutations involved in treatment resistance. Furthermore, ctDNA may inform about timing and potential cooperation of multiple driver genes aberration guiding the treatment options in patients with mCRPC. However, the clinical use of ctDNA test in prostate cancer compared to blood and tissue testing are currently very limited. In this review, we summarize the current therapeutic indications in prostate cancer patients with DDR deficiency, the recommendation for germline and somatic-genomic testing in advanced PC and the advantages of the use liquid biopsy in clinical routine for mCRPC.
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Affiliation(s)
- Martina Catalano
- School of Human Health Sciences, University of Florence, Florence, Italy
| | - Daniele Generali
- Department of Medical, Surgical and Health Sciences, University of Trieste, Cattinara Hospital Trieste, Trieste, Italy
| | - Marta Gatti
- Servizio di Citogenetica e Genetica - Azienda Socio-Sanitaria Territoriale (ASST) di Cremona, Cremona, Italy
| | - Barbara Riboli
- Servizio di Citogenetica e Genetica - Azienda Socio-Sanitaria Territoriale (ASST) di Cremona, Cremona, Italy
| | - Leda Paganini
- Servizio di Citogenetica e Genetica - Azienda Socio-Sanitaria Territoriale (ASST) di Cremona, Cremona, Italy
| | - Gabriella Nesi
- Department of Health Sciences, University of Florence, Florence, Italy
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21
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Lin Z, Wang T, Li H, Xiao M, Ma X, Gu Y, Qiang J. Magnetic resonance-based radiomics nomogram for predicting microsatellite instability status in endometrial cancer. Quant Imaging Med Surg 2023; 13:108-120. [PMID: 36620141 PMCID: PMC9816750 DOI: 10.21037/qims-22-255] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 09/05/2022] [Indexed: 11/30/2022]
Abstract
Background Microsatellite instability (MSI) status is an important indicator for screening patients with endometrial cancer (EC) who have potential Lynch syndrome (LS) and may benefit from immunotherapy. This study aimed to develop a magnetic resonance imaging (MRI)-based radiomics nomogram for the prediction of MSI status in EC. Methods A total of 296 patients with histopathologically diagnosed EC were enrolled, and their MSI status was determined using immunohistochemical (IHC) analysis. Patients were randomly divided into the training cohort (n=236) and the validation cohort (n=60) at a ratio of 8:2. To predict the MSI status in EC, the tumor radiomics features were extracted from T2-weighted images and contrast-enhanced T1-weighted images, which in turn were selected using one-way analysis of variance (ANOVA) and the least absolute shrinkage and selection operator (LASSO) algorithm to build the radiomics signature (radiomics score; radscore) model. Five clinicopathologic characteristics were used to construct a clinicopathologic model. Finally, the nomogram model combining radscore and clinicopathologic characteristics was constructed. The performance of the three models was evaluated using receiver operating characteristic (ROC), calibration, and decision curve analyses (DCA). Results Totals of 21 radiomics features and five clinicopathologic characteristics were selected to develop the radscore and clinicopathological models. The radscore and clinicopathologic models achieved an area under the curve (AUC) of 0.752 and 0.600, respectively, in the training cohort; and of 0.723 and 0.615, respectively, in the validation cohort. The radiomics nomogram model showed improved discrimination efficiency compared with the radscore and clinicopathologic models, with an AUC of 0.773 and 0.740 in the training and validation cohorts, respectively. The calibration curve analysis and DCA showed favorable calibration and clinical utility of the nomogram model. Conclusions The nomogram incorporating MRI-based radiomics features and clinicopathologic characteristics could be a potential tool for the prediction of MSI status in EC.
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Affiliation(s)
- Zijing Lin
- Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ting Wang
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
| | - Haiming Li
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Meiling Xiao
- Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China
| | - Xiaoliang Ma
- Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China
| | - Yajia Gu
- Department of Radiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jinwei Qiang
- Department of Radiology, Jinshan Hospital, Fudan University, Shanghai, China
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22
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Amemiya K, Hirotsu Y, Nagakubo Y, Watanabe S, Amemiya S, Mochizuki H, Oyama T, Kondo T, Omata M. Simple IHC reveals complex MMR alternations than PCR assays: Validation by LCM and next-generation sequencing. Cancer Med 2022; 11:4479-4490. [PMID: 35596629 PMCID: PMC9741978 DOI: 10.1002/cam4.4832] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 04/07/2022] [Accepted: 05/04/2022] [Indexed: 12/15/2022] Open
Abstract
Evaluation of the status of mismatch repair (MMR) in tumors is crucial for determining the application of immune checkpoint inhibitors (ICIs). Conventional PCR (MSI-PCR) is the gold standard for confirming the MMR status. However, it requires visual confirmation and presents difficulties in determining MMR status. Immunohistochemistry (IHC) is a simple method and can confirming MMR protein expression in the whole tumor. We aim to investigate IHC is more suitable for evaluating MMR status in the tumor. We compared MSI-PCR and IHC by testing 319 samples from 284 patients across 14 cancer types. In discordant cases, we performed laser-capture microdissection and microsatellite instability assay by next-generation sequencing (MSI-NGS). The concordance rate between IHC and MSI-PCR testing was 98.1% (313/319). Two reasons for these discrepancies were ambiguous MSI-PCR results and heterogeneous MSI status within the tumor. Among six cases (1.9%), three were judged as MSI-H by MSI-PCR but with proficient MMR by IHC. The results of MSI-NGS revealed microsatellite stable in these three cases. The remaining three cases, two of three were MSI-H and one was MSS in whole tumor in MSI-PCR. IHC showed a "mosaic" pattern containing both proficient MMR and deficient MMR portions by IHC in all three cases. We performed microdissection and MSI-PCR and found intratumoral heterogeneity of MMR status. These results indicated the advantages of IHC and performed expanded samples (n = 1082) and two additional mosaic cases were identified. Our results clearly indicated that simple IHC is the best choice for determining MMR alterations in critical cases for ICIs treatment.
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Affiliation(s)
- Kenji Amemiya
- Division of Genetics and Clinical LaboratoryYamanashi Cental HospitalYamanashiJapan
- Genome Analysis CenterYamanashi Cental HospitalYamanashiJapan
- Department of Pathology, School of MedicineUniversity of YamanashiYamanashiJapan
| | - Yosuke Hirotsu
- Division of Genetics and Clinical LaboratoryYamanashi Cental HospitalYamanashiJapan
- Genome Analysis CenterYamanashi Cental HospitalYamanashiJapan
| | - Yuki Nagakubo
- Division of Genetics and Clinical LaboratoryYamanashi Cental HospitalYamanashiJapan
| | | | - Saki Amemiya
- Department of PathologyYamanashi Central HospitalYamanashiJapan
| | | | - Toshio Oyama
- Department of PathologyYamanashi Central HospitalYamanashiJapan
| | - Tetsuo Kondo
- Department of Pathology, School of MedicineUniversity of YamanashiYamanashiJapan
| | - Masao Omata
- Department of GastroenterologyYamanashi Central HospitalYamanashiJapan
- Department of GastroenterologyThe University of TokyoTokyoJapan
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Akhoundova D, Feng FY, Pritchard CC, Rubin MA. Molecular Genetics of Prostate Cancer and Role of Genomic Testing. Surg Pathol Clin 2022; 15:617-628. [PMID: 36344179 DOI: 10.1016/j.path.2022.08.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/16/2023]
Abstract
Prostate cancer (PCa) is characterized by profound genomic heterogeneity. Recent advances in personalized treatment entail an increasing need of genomic profiling. For localized PCa, gene expression assays can support clinical decisions regarding active surveillance and adjuvant treatment. In metastatic PCa, homologous recombination deficiency, microsatellite instability-high (MSI-H), and CDK12 deficiency constitute main actionable alterations. Alterations in DNA repair genes confer variable sensitivities to poly(ADP-ribose)polymerase inhibitors, and the use of genomic instability assays as predictive biomarker is still incipient. MSI can be assessed by immunohistochemistry To date there is a lack of consensus as to testing standards.
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Affiliation(s)
- Dilara Akhoundova
- Department for BioMedical Research, University of Bern, Murtenstrasse 24, Bern 3008, Switzerland; Department of Medical Oncology, Inselspital, University Hospital of Bern, Bern 3010, Switzerland
| | - Felix Y Feng
- Department of Radiation Oncology, University of California, 1600 Divisadero Street, Suite H-1031, San Francisco, CA 94115, USA
| | - Colin C Pritchard
- Department of Laboratory Medicine and Pathology, University of Washington, 1959 NE Pacific St Seattle, WA 98195-7110, USA
| | - Mark A Rubin
- Department for BioMedical Research, University of Bern, Murtenstrasse 24, Bern 3008, Switzerland; Bern Center for Precision Medicine, Inselspital, University Hospital of Bern, Bern, 3008, Switzerland.
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24
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Morales-Juarez DA, Jackson SP. Clinical prospects of WRN inhibition as a treatment for MSI tumours. NPJ Precis Oncol 2022; 6:85. [PMID: 36379964 PMCID: PMC9666358 DOI: 10.1038/s41698-022-00319-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2022] [Accepted: 10/06/2022] [Indexed: 11/17/2022] Open
Abstract
The discovery of synthetic lethal interactions with genetic deficiencies in cancers has highlighted several candidate targets for drug development, with variable clinical success. Recent work has unveiled a promising synthetic lethal interaction between inactivation/inhibition of the WRN DNA helicase and tumours with microsatellite instability, a phenotype that arises from DNA mismatch repair deficiency. While these and further studies have highlighted the therapeutic potential of WRN inhibitors, compounds with properties suitable for clinical exploitation remain to be described. Furthermore, the complexities of MSI development and its relationship to cancer evolution pose challenges for clinical prospects. Here, we discuss possible paths of MSI tumour development, the viability of WRN inhibition as a strategy in different scenarios, and the necessary conditions to create a roadmap towards successful implementation of WRN inhibitors in the clinic.
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Affiliation(s)
- David A Morales-Juarez
- Wellcome and Cancer Research UK Gurdon Institute, and Department of Biochemistry, University of Cambridge, Cambridge, UK.
| | - Stephen P Jackson
- Wellcome and Cancer Research UK Gurdon Institute, and Department of Biochemistry, University of Cambridge, Cambridge, UK.
- Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK.
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25
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Kulkarni A, Wafik M. Genomics makes prostate cancer personal. TRENDS IN UROLOGY & MEN'S HEALTH 2022. [DOI: 10.1002/tre.883] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
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Bartley AN, Mills AM, Konnick E, Overman M, Ventura CB, Souter L, Colasacco C, Stadler ZK, Kerr S, Howitt BE, Hampel H, Adams SF, Johnson W, Magi-Galluzzi C, Sepulveda AR, Broaddus RR. Mismatch Repair and Microsatellite Instability Testing for Immune Checkpoint Inhibitor Therapy: Guideline From the College of American Pathologists in Collaboration With the Association for Molecular Pathology and Fight Colorectal Cancer. Arch Pathol Lab Med 2022; 146:1194-1210. [PMID: 35920830 DOI: 10.5858/arpa.2021-0632-cp] [Citation(s) in RCA: 66] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/07/2022] [Indexed: 11/06/2022]
Abstract
CONTEXT.— The US Food and Drug Administration (FDA) approved immune checkpoint inhibitor therapy for patients with advanced solid tumors that have DNA mismatch repair defects or high levels of microsatellite instability; however, the FDA provided no guidance on which specific clinical assays should be used to determine mismatch repair status. OBJECTIVE.— To develop an evidence-based guideline to identify the optimal clinical laboratory test to identify defects in DNA mismatch repair in patients with solid tumor malignancies who are being considered for immune checkpoint inhibitor therapy. DESIGN.— The College of American Pathologists convened an expert panel to perform a systematic review of the literature and develop recommendations. Using the National Academy of Medicine-endorsed Grading of Recommendations Assessment, Development and Evaluation approach, the recommendations were derived from available evidence, strength of that evidence, open comment feedback, and expert panel consensus. Mismatch repair immunohistochemistry, microsatellite instability derived from both polymerase chain reaction and next-generation sequencing, and tumor mutation burden derived from large panel next-generation sequencing were within scope. RESULTS.— Six recommendations and 3 good practice statements were developed. More evidence and evidence of higher quality were identified for colorectal cancer and other cancers of the gastrointestinal (GI) tract than for cancers arising outside the GI tract. CONCLUSIONS.— An optimal assay depends on cancer type. For most cancer types outside of the GI tract and the endometrium, there was insufficient published evidence to recommend a specific clinical assay. Absent published evidence, immunohistochemistry is an acceptable approach readily available in most clinical laboratories.
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Affiliation(s)
- Angela N Bartley
- From the Department of Pathology, St. Joseph Mercy Hospital, Ann Arbor, Michigan (Bartley)
| | - Anne M Mills
- From the Department of Pathology, University of Virginia, Charlottesville (Mills)
| | - Eric Konnick
- From the Department of Laboratory Medicine and Pathology, University of Washington, Seattle (Konnick)
| | - Michael Overman
- From the Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston (Overman)
| | - Christina B Ventura
- From Surveys, College of American Pathologists, Northfield, Illinois (Ventura, Colasacco)
| | - Lesley Souter
- From Methodology Consultant, Smithville, Ontario, Canada (Souter)
| | - Carol Colasacco
- From Surveys, College of American Pathologists, Northfield, Illinois (Ventura, Colasacco)
| | - Zsofia K Stadler
- From the Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York (Stadler)
| | - Sarah Kerr
- From Hospital Pathology Associates, PA, Minneapolis, Minnesota (Kerr)
| | - Brooke E Howitt
- From the Department of Pathology, Stanford University, Stanford, California (Howitt)
| | - Heather Hampel
- From the Department of Internal Medicine, The Ohio State University, Columbus (Hampel)
| | - Sarah F Adams
- From the Department of Obstetrics & Gynecology, University of New Mexico, Albuquerque (Adams)
| | - Wenora Johnson
- From Fight Colorectal Cancer, Springfield, Missouri (Johnson)
| | - Cristina Magi-Galluzzi
- From the Department of Pathology, University of Alabama at Birmingham, Birmingham (Magi-Galluzzi)
| | - Antonia R Sepulveda
- From the Department of Pathology, George Washington University, Washington, District of Columbia (Sepulveda)
| | - Russell R Broaddus
- From the Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill (Broaddus)
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Malik A, Bhatia JK, Sahai K, Boruah D, Sharma A. Evaluating morphological features for predicting microsatellite instability status in colorectal cancer. Med J Armed Forces India 2022; 78:S96-S104. [PMID: 36147411 PMCID: PMC9485851 DOI: 10.1016/j.mjafi.2021.03.024] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2019] [Accepted: 03/28/2021] [Indexed: 10/20/2022] Open
Abstract
Background Colorectal cancer (CRC) is one of the commonest cancers worldwide, with incidence rates in India being around 4%. It is a heterogeneous disease with multiple established prognostic factors. Ten to fifteen percent originate from microsatellite instability (MSI) pathway, characterized by defect in mismatch repair (MMR) gene. Identification of MMR defective protein is relevant for diagnosis, prognosis, and prediction. Certain clinical and histological features are known to be associated with defective MMR genes. The objectives of this study are to find the prevalence of MSI in CRC to identify features associated with MSI and assess the value of histopathology in predicting MSI. Methods We evaluated various clinical and histological parameters for identifying prognostically favorable colon cancers in a tertiary hospital. One hundred fifty colon cancers were evaluated, and MSI status was correlated with clinicopathologic variables. Results The prevalence of MSI in CRC was found to be 11.3%. The factors associated with MSI were tumor differentiation, stage, tumor site, tumor size, tumor-infiltrating lymphocytes, Crohn's-like lymphoid reaction, and dirty necrosis. We have defined a "P" score for prediction of MSI using the clinicohistological parameters, which could be used to select patients who are to be tested for MSI. Conclusion Assessment of clinical and histopathological features will help in patient stratification and selection of patients for MSI testing. The evaluation is economical, reproducible, and easy to apply.
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Affiliation(s)
| | - Jasvinder Kaur Bhatia
- Senior Adviser & Head (Pathology), Command Hospital (Eastern Command) Kolkata, India
| | | | - Dibyajyoti Boruah
- Scientist ‘E’, Department of Pathology, Armed Forces Medical College, Pune, India
| | - A. Sharma
- Classified Specialist (Pathology), INHS Kalyani, Visakhapatnam, India
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Graham LS, Schweizer MT. Mismatch repair deficiency and clinical implications in prostate cancer. Prostate 2022; 82 Suppl 1:S37-S44. [PMID: 35358351 DOI: 10.1002/pros.24343] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 03/09/2022] [Accepted: 03/14/2022] [Indexed: 12/11/2022]
Abstract
Despite recent therapeutic advances, castration-resistant prostate cancer (CRPC) remains a lethal disease and novel therapies are needed. Precision oncology provides an avenue for developing effective tailored approaches for treating malignancies based on a tumor's molecular profile. Indeed, the presence of mismatch repair deficiency (MMRd) has proven to be an important predictive biomarker for response to immune checkpoint blockade across multiple tumor types, including prostate cancer, and represents a major precision oncology success story. The mismatch repair (MMR) system is integral to maintaining genomic fidelity during cellular replication. Cancers with deficiencies in this system accumulate high numbers of mutations and express many neoantigens that may be recognized by the immune system. The checkpoint inhibitor pembrolizumab has recently been approved for all cancers that are MMR deficient, and several retrospective series have specifically shown that pembrolizumab is effective in MMRd prostate cancer. Although the prevalence of MMRd in CRPC is low (approximately 3%-5% of cases), this is an important subset of men that require a unique therapeutic approach. This review will focus on MMRd in prostate cancer, highlighting the clinical implications, role of immunotherapy, and areas of future research.
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Affiliation(s)
- Laura S Graham
- Division of Medical Oncology, University of Colorado, Aurora, Colorado, USA
| | - Michael T Schweizer
- Division of Medical Oncology, University of Washington, Seattle, Washington, USA
- Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA
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29
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Bosch DE, Yeh MM, Salipante SJ, Jacobson A, Cohen SA, Konnick EQ, Paulson VA. Isolated MLH1 Loss by Immunohistochemistry Because of Benign Germline MLH1 Polymorphisms. JCO Precis Oncol 2022; 6:e2200227. [PMID: 36044719 PMCID: PMC9489174 DOI: 10.1200/po.22.00227] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
Mismatch repair (MMR) immunohistochemistry (IHC) is frequently used to inform prognosis, select (immuno-)therapy, and identify patients for heritable cancer syndrome testing. However, false-negative and false-positive MMR IHC interpretations have been described.
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Affiliation(s)
- Dustin E Bosch
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA.,Department of Pathology, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, IA
| | - Matthew M Yeh
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA
| | - Stephen J Salipante
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA
| | - Angela Jacobson
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA
| | - Stacey A Cohen
- Division of Medical Oncology, Department of Medicine, University of Washington School of Medicine, Seattle, WA.,Clinical Research Division, Fred Hutchinson Cancer Research Center, Seattle, WA
| | - Eric Q Konnick
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA
| | - Vera A Paulson
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, WA
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30
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Chiu PKF, Lee EKC, Chan MTY, Chan WHC, Cheung MH, Lam MHC, Ma ESK, Poon DMC. Genetic Testing and Its Clinical Application in Prostate Cancer Management: Consensus Statements from the Hong Kong Urological Association and Hong Kong Society of Uro-Oncology. Front Oncol 2022; 12:962958. [PMID: 35924163 PMCID: PMC9339641 DOI: 10.3389/fonc.2022.962958] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2022] [Accepted: 06/24/2022] [Indexed: 11/17/2022] Open
Abstract
Background In recent years, indications for genetic testing in prostate cancer (PC) have expanded from patients with a family history of prostate and/or related cancers to those with advanced castration-resistant disease, and even to early PC patients for determination of the appropriateness of active surveillance. The current consensus aims to provide guidance to urologists, oncologists and pathologists working with Asian PC patients on who and what to test for in selected populations. Methods A joint consensus panel from the Hong Kong Urological Association and Hong Kong Society of Uro-Oncology was convened over a series of 5 physical and virtual meetings. A background literature search on genetic testing in PC was performed in PubMed, ClinicalKey, EBSCOHost, Ovid and ProQuest, and three working subgroups were formed to review and present the relevant evidence. Meeting agendas adopted a modified Delphi approach to ensure that discussions proceed in a structured, iterative and balanced manner, which was followed by an anonymous voting on candidate statements. Of 5 available answer options, a consensus statement was accepted if ≥ 75% of the panelists chose “Accept Completely” (Option A) or “Accept with Some Reservation” (Option B). Results The consensus was structured into three parts: indications for testing, testing methods, and therapeutic implications. A list of 35 candidate statements were developed, of which 31 were accepted. The statements addressed questions on the application of PC genetic testing data and guidelines to Asian patients, including patient selection for germline testing, selection of gene panel and tissue sample, provision of genetic counseling, and use of novel systemic treatments in metastatic castration-resistant PC patients. Conclusion This consensus provides guidance to urologists, oncologists and pathologists working with Asian patients on indications for genetic testing, testing methods and technical considerations, and associated therapeutic implications.
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Affiliation(s)
- Peter K. F. Chiu
- S.H. Ho Urology Centre, Department of Surgery, The Chinese University of Hong Kong, Hong Kong SAR, China
| | - Eric K. C. Lee
- Department of Clinical Oncology, Tuen Mun Hospital, Hong Kong SAR, China
| | - Marco T. Y. Chan
- Division of Urology, Department of Surgery, Tuen Mun Hospital, Hong Kong SAR, China
| | - Wilson H. C. Chan
- Division of Urology, Department of Surgery, United Christian Hospital, Hong Kong SAR, China
| | - M. H. Cheung
- Division of Urology, Department of Surgery, Tseung Kwan O Hospital, Hong Kong SAR, China
| | - Martin H. C. Lam
- Department of Oncology, United Christian Hospital, Hong Kong SAR, China
| | - Edmond S. K. Ma
- Department of Pathology, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China
| | - Darren M. C. Poon
- Department of Clinical Oncology, State Key Laboratory of Translational Oncology, Sir YK Pao Centre for Cancer, Hong Kong Cancer Institute, The Chinese University of Hong Kong, Hong Kong SAR, China
- Comprehensive Oncology Centre, Hong Kong Sanatorium and Hospital, Hong Kong SAR, China
- *Correspondence: Darren M. C. Poon,
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31
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Interpretable tumor differentiation grade and microsatellite instability recognition in gastric cancer using deep learning. J Transl Med 2022; 102:641-649. [PMID: 35177797 DOI: 10.1038/s41374-022-00742-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2021] [Revised: 01/18/2022] [Accepted: 01/22/2022] [Indexed: 12/13/2022] Open
Abstract
Gastric cancer possesses great histological and molecular diversity, which creates obstacles for rapid and efficient diagnoses. Classic diagnoses either depend on the pathologist's judgment, which relies heavily on subjective experience, or time-consuming molecular assays for subtype diagnosis. Here, we present a deep learning (DL) system to achieve interpretable tumor differentiation grade and microsatellite instability (MSI) recognition in gastric cancer directly using hematoxylin-eosin (HE) staining whole-slide images (WSIs). WSIs from 467 patients were divided into three cohorts: the training cohort with 348 annotated WSIs, the testing cohort with 88 annotated WSIs, and the integration testing cohort with 31 original WSIs without tumor contour annotation. First, the DL models comprehensibly achieved tumor differentiation recognition with an F1 values of 0.8615 and 0.8977 for poorly differentiated adenocarcinoma (PDA) and well-differentiated adenocarcinoma (WDA) classes. Its ability to extract pathological features about the glandular structure formation, which is the key to distinguishing between PDA and WDA, increased the interpretability of the DL models. Second, the DL models achieved MSI status recognition with a patient-level accuracy of 86.36% directly from HE-stained WSIs in the testing cohort. Finally, the integrated end-to-end system achieved patient-level MSI recognition from original HE staining WSIs with an accuracy of 83.87% in the integration testing cohort with no tumor contour annotation. The proposed system, therefore, demonstrated high accuracy and interpretability, which can potentially promote the implementation of artificial intelligence healthcare.
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32
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Nakamura Y, Okamoto W, Denda T, Nishina T, Komatsu Y, Yuki S, Yasui H, Esaki T, Sunakawa Y, Ueno M, Shinozaki E, Matsuhashi N, Ohta T, Kato K, Ohtsubo K, Bando H, Hara H, Satoh T, Yamazaki K, Yamamoto Y, Okano N, Terazawa T, Kato T, Oki E, Tsuji A, Horita Y, Hamamoto Y, Kawazoe A, Nakajima H, Nomura S, Mitani R, Yuasa M, Akagi K, Yoshino T. Clinical Validity of Plasma-Based Genotyping for Microsatellite Instability Assessment in Advanced GI Cancers: SCRUM-Japan GOZILA Substudy. JCO Precis Oncol 2022; 6:e2100383. [PMID: 35188805 PMCID: PMC8974570 DOI: 10.1200/po.21.00383] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2021] [Revised: 11/21/2021] [Accepted: 01/12/2022] [Indexed: 12/21/2022] Open
Abstract
PURPOSE Circulating tumor DNA (ctDNA) genotyping may guide targeted therapy for patients with advanced GI cancers. However, no studies have validated ctDNA genotyping for microsatellite instability (MSI) assessment in comparison with a tissue-based standard. PATIENTS AND METHODS The performance of plasma-based MSI assessment using Guardant360, a next-generation sequencing-based ctDNA assay, was compared with that of tissue-based MSI assessment using a validated polymerase chain reaction-based method in patients with advanced GI cancers enrolled in GOZILA study, a nationwide ctDNA profiling study. The primary end points were overall percent agreement, positive percent agreement (PPA), and negative percent agreement. The efficacy of immune checkpoint inhibitor therapy was also evaluated. RESULTS In 658 patients with advanced GI cancers who underwent both plasma and tissue testing for MSI, the overall percent agreement, PPA, and negative percent agreement were 98.2% (95% CI, 96.8 to 99.1), 71.4% (95% CI, 47.8 to 88.7), and 99.1% (95% CI, 98.0 to 99.7), respectively. In patients whose plasma samples had a ctDNA fraction ≥ 1.0%, the PPA was 100.0% (15/15; 95% CI, 78.2 to 100.0). Three patients with MSI-high (MSI-H) tumors detected only by ctDNA genotyping achieved clinical benefits after receiving anti-programmed cell death 1 therapy with the progression-free survival ranging from 4.3 to 16.7 months. One patient with an aggressive cancer of an unknown primary site benefited from pembrolizumab after rapid detection of MSI-H by ctDNA genotyping. CONCLUSION ctDNA genotyping was able to detect MSI with high concordance to validated tissue-based MSI testing, especially in patients with tumors that have sufficient ctDNA shedding. Furthermore, ctDNA genotyping enabled identification of patients with MSI-H tumors who benefited from immune checkpoint inhibitor treatment.
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Affiliation(s)
- Yoshiaki Nakamura
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan
| | - Wataru Okamoto
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan
- Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan
| | - Tadamichi Denda
- Division of Gastroenterology, Chiba Cancer Center, Chiba, Japan
| | - Tomohiro Nishina
- Gastrointestinal Medical Oncology, National Hospital Organization Shikoku Cancer Center, Matsuyama, Japan
| | - Yoshito Komatsu
- Department of Cancer Center, Hokkaido University Hospital, Sapporo, Japan
| | - Satoshi Yuki
- Department of Gastroenterology and Hepatology, Hokkaido University Hospital, Sapporo, Japan
| | - Hisateru Yasui
- Department of Medical Oncology, Kobe City Medical Center General Hospital, Kobe, Japan
| | - Taito Esaki
- Department of Gastrointestinal and Medical Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, Japan
| | - Yu Sunakawa
- Department of Clinical Oncology, St Marianna University School of Medicine, Kawasaki, Japan
| | - Makoto Ueno
- Department of Gastroenterology, Hepatobiliary and Pancreatic Medical Oncology Division, Kanagawa Cancer Center, Yokohama, Japan
| | - Eiji Shinozaki
- Department of Gastroenterological Chemotherapy, Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, Japan
| | - Nobuhisa Matsuhashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Gifu University, Gifu, Japan
| | - Takashi Ohta
- Department of Clinical Oncology, Kansai Rosai Hospital, Amagasaki, Japan
| | - Ken Kato
- Department of Head and Neck, Esophageal Medical Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Koushiro Ohtsubo
- Division of Medical Oncology, Cancer Research Institute, Kanazawa University, Kanazawa, Japan
| | - Hideaki Bando
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
- Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan
- Department of Clinical Oncology, Aichi Cancer Center, Nagoya, Japan
| | - Hiroki Hara
- Department of Gastroenterology, Saitama Cancer Center, Ina, Japan
| | - Taroh Satoh
- Department of Frontier Science for Cancer and Chemotherapy, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Kentaro Yamazaki
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Nagaizumi, Japan
| | - Yoshiyuki Yamamoto
- Department of Gastroenterology, University of Tsukuba Hospital, Tsukuba, Japan
| | - Naohiro Okano
- Department of Medical Oncology, Kyorin University Faculty of Medicine, Mitaka, Japan
| | - Tetsuji Terazawa
- Cancer Chemotherapy Center, Osaka Medical College Hospital, Takatsuki, Japan
| | - Takeshi Kato
- Department of Surgery, National Hospital Organization Osaka National Hospital, Osaka, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Akihito Tsuji
- Department of Clinical Oncology, Kagawa University Hospital, Miki, Japan
| | - Yosuke Horita
- Department of Medical Oncology, Saitama Medical University International Medical Center, Hidaka, Japan
| | - Yasuo Hamamoto
- Keio Cancer Center, Keio University School of Medicine, Tokyo, Japan
| | - Akihito Kawazoe
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Hiromichi Nakajima
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
| | - Shogo Nomura
- Clinical Research Support Office, National Cancer Center Hospital East, Kashiwa, Japan
| | - Ryuta Mitani
- Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan
| | - Mihoko Yuasa
- Translational Research Support Section, National Cancer Center Hospital East, Kashiwa, Japan
| | - Kiwamu Akagi
- Department of Molecular Diagnosis and Cancer Prevention, Saitama Cancer Center, Ina, Japan
| | - Takayuki Yoshino
- Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan
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Assessment of Microsatellite Instability from Next-Generation Sequencing Data. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2022; 1361:75-100. [DOI: 10.1007/978-3-030-91836-1_5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/19/2022]
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Jaffrelot M, Farés N, Brunac AC, Laurenty AP, Danjoux M, Grand D, Icher S, Meilleroux J, Mery E, Buscail E, Maulat C, Toulas C, Vande Perre P, Chipoulet E, Bonnet D, Staub A, Guimbaud R, Selves J. An unusual phenotype occurs in 15% of mismatch repair-deficient tumors and is associated with non-colorectal cancers and genetic syndromes. Mod Pathol 2022; 35:427-437. [PMID: 34545179 PMCID: PMC8860743 DOI: 10.1038/s41379-021-00918-3] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2020] [Revised: 08/21/2021] [Accepted: 08/27/2021] [Indexed: 02/07/2023]
Abstract
Immunohistochemistry (IHC) and/or MSI-PCR (microsatellite instability-polymerase chain reaction) tests are performed routinely to detect mismatch repair deficiency (MMR-D). Classical MMR-D tumors present a loss of MLH1/PMS2 or MSH2/MSH6 with MSI-High. Other profiles of MMR-D tumors have been described but have been rarely studied. In this study, we established a classification of unusual MMR-D tumors and determined their frequency and clinical impact. All MMR-D tumors identified between 2007 and 2017 were selected. Any profile besides the classical MMR-D phenotype was defined as unusual. For patients with unusual MMR-D tumors, IHC, and PCR data were reviewed, the tumor mutation burden (TMB) was evaluated and clinical and genetic features were collected. Of the 4948 cases of MMR testing, 3800 had both the available IHC and MSI-PCR results and 585 of these had MMR-D. After reviewing the IHC and PCR, 21% of the cases initially identified as unusual MMR-D were reclassified, which resulted in a final identification of 89 unusual MMR-D tumors (15%). Unusual MMR-D tumors were more often associated with non-CRC than classical MMR-D tumors. Unusual MMR-D tumors were classified into four sub-groups: i) isolated loss of PMS2 or MSH6, ii) classical loss of MLH1/PMS2 or MSH2/MSH6 without MSI, iii) four MMR proteins retained with MSI and, iv) complex loss of MMR proteins, with clinical characteristics for each sub-group. TMB-high or -intermediate was shown in 96% of the cancers studied (24/25), which confirmed MMR deficiency. Genetic syndromes were identified in 44.9% (40/89) and 21.4% (106/496) of patients with unusual and classical MMR-D tumors, respectively (P < 0.001). Five patients treated with an immune checkpoint inhibitor (ICI) had a prolonged clinical benefit. Our classification of unusual MMR-D phenotype helps to identify MMR deficiency. Unusual MMR-D phenotype occurs in 15% of MMR-D tumors. A high frequency of genetic syndromes was noted in these patients who could benefit from ICI.
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Affiliation(s)
- Marion Jaffrelot
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Nadim Farés
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France ,grid.15781.3a0000 0001 0723 035XUniversité Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330 Toulouse, France ,grid.411175.70000 0001 1457 2980Department of Digestive Surgery, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Anne Cécile Brunac
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Anne Pascale Laurenty
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Marie Danjoux
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - David Grand
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Samira Icher
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Julie Meilleroux
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Eliane Mery
- grid.411175.70000 0001 1457 2980Department of Pathology, Institut Universitaire du Cancer-Oncopole de Toulouse; Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Etienne Buscail
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Charlotte Maulat
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Christine Toulas
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Pierre Vande Perre
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Edith Chipoulet
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Delphine Bonnet
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Anne Staub
- grid.411175.70000 0001 1457 2980Department of Oncogenetics, Institut Universitaire du Cancer-Oncopole de Toulouse, Institut Claudius Regaud and Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Rosine Guimbaud
- grid.411175.70000 0001 1457 2980Department of Digestive Oncology, Centre Hospitalier Universitaire (CHU), Toulouse, France ,grid.15781.3a0000 0001 0723 035XUniversité Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330 Toulouse, France ,grid.411175.70000 0001 1457 2980Department of Digestive Surgery, Centre Hospitalier Universitaire (CHU), Toulouse, France
| | - Janick Selves
- Université Fédérale Toulouse Midi-Pyrénées, Université Toulouse III Paul Sabatier, INSERM, CRCT, 31330, Toulouse, France. .,Department of Digestive Surgery, Centre Hospitalier Universitaire (CHU), Toulouse, France.
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Ottini A, Sepe P, Beninato T, Claps M, Guadalupi V, Verzoni E, Giannatempo P, Baciarello G, de Braud F, Procopio G. Biomarker-driven immunotherapy for precision medicine in prostate cancer. Per Med 2021; 19:51-66. [PMID: 34873959 DOI: 10.2217/pme-2021-0079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Although immunotherapy has recently revolutionized standard of care in different cancer types, prostate cancer has generally failed to show dramatic responses to immune checkpoint inhibitors. As in other tumors, the goal in prostate cancer is now to target treatments more precisely on patient's individual characteristics through precision medicine. Defects in mismatch repair, mutations in the exonuclease domain of the DNA polymerase epsilon (POLE), high tumor mutational burden and the presence of biallelic loss of CDK12 among others, are predictive biomarkers of response to immunotherapy. In the present review, we summarize the evolving landscape of immunotherapy in prostate cancer, including precision approaches and strategies to define classes of responsive patients and scale up resistance to immune checkpoint inhibitors.
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Affiliation(s)
- Arianna Ottini
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Pierangela Sepe
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Teresa Beninato
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Mélanie Claps
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Valentina Guadalupi
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Elena Verzoni
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Patrizia Giannatempo
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giulia Baciarello
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Filippo de Braud
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
| | - Giuseppe Procopio
- Department of Medical Oncology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
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36
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Lin JH, Chen S, Pallavajjala A, Guedes LB, Lotan TL, Bacher JW, Eshleman JR. Validation of Long Mononucleotide Repeat Markers for Detection of Microsatellite Instability. J Mol Diagn 2021; 24:144-157. [PMID: 34864149 DOI: 10.1016/j.jmoldx.2021.10.011] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2021] [Revised: 09/23/2021] [Accepted: 10/27/2021] [Indexed: 01/22/2023] Open
Abstract
Mismatch repair deficiency (dMMR) predicts response to immune checkpoint inhibitor therapy in solid tumors. Long mononucleotide repeat (LMR) markers may improve the interpretation of microsatellite instability (MSI) assays. Our cohorts included mismatch repair (MMR) proficient and dMMR colorectal cancer (CRC) samples, MMR proficient and dMMR endometrial cancer (EC) samples, dMMR prostate cancer samples, MSI-high (MSI-H) samples of other cancer types, and MSI-low (MSI-L) samples of various cancer types. MMR status was determined by immunohistochemical staining and/or MSI Analysis System Version 1.2 (V1.2). The sensitivity and specificity of the LMR MSI panel for dMMR detection were both 100% in CRC. The sensitivity values of the MSI V1.2 and LMR MSI panels in EC were 88% and 98%, respectively, and the specificity values were both 100%. The sensitivity of the LMR panel was 75% in dMMR prostate cancer detected by immunohistochemistry. The 22 samples of other cancer types that were previously classified as MSI-H were also classified as MSI-H using the LMR MSI panel. For the 12 samples that were previously classified as MSI-L, 1 sample was classified as microsatellite stable using the LMR MSI panel, 8 as MSI-L, and 3 as MSI-H. The LMR MSI panel showed high concordance to the MSI V1.2 panel in CRC and greater sensitivity in EC. The LMR MSI panel improves dMMR detection in noncolorectal cancers.
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Affiliation(s)
- John H Lin
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Suping Chen
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Aparna Pallavajjala
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Liana B Guedes
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Tamara L Lotan
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | | | - James R Eshleman
- The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland; The Sol Goldman Pancreatic Cancer Research Center, Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, Maryland.
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37
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Zhao C, Liu Y, Ju S, Wang X. Pan-Cancer Analysis of the N6-Methyladenosine Eraser FTO as a Potential Prognostic and Immunological Biomarker. Int J Gen Med 2021; 14:7411-7422. [PMID: 34744452 PMCID: PMC8565892 DOI: 10.2147/ijgm.s331752] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2021] [Accepted: 09/10/2021] [Indexed: 12/11/2022] Open
Abstract
Background Fat mass and obesity-associated protein (FTO) is a critical N6-methyladenosine (m6A) demethylase that participates in tumorigenesis and is associated with the prognosis of patients in some cancers. However, the key roles of FTO in pan-cancer are still largely obscure. Methods FTO expression levels in pan-cancer were estimated via the Genotype-Tissue Expression (GTEx), Cancer Cell Line Encyclopedia (CCLE), and The Cancer Genome Atlas (TCGA) databases. Univariate survival analysis was used to estimate the effects of FTO on prognosis. In addition, we used the Tumor Immune Evaluation Resource (TIMER) to assess the immune cell infiltration of FTO gene across cancers. The association of FTO expression with immune checkpoint genes expression, DNA mismatch repair (MMR) gene mutation, DNA methyltransferases, microsatellite instability (MSI), and tumor mutational burden (TMB) was investigated using Spearman’s correlation analysis. Moreover, Gene Set Enrichment Analysis (GSEA) was utilized to identify critical pathways in cancers. The STRING website was used to reveal the protein–protein interaction (PPI) network of FTO. Results FTO was aberrantly expressed across cancers and survival analysis demonstrated that its expression was associated with clinical prognosis of many cancer patients. Specifically, FTO expression was significantly associated with immune infiltrating cells in colon adenocarcinoma, kidney renal clear cell carcinoma, and liver hepatocellular carcinoma. In addition, FTO expression was significantly associated with immune checkpoint genes expression, MMR, DNA methyltransferases levels, TMB, and MSI in multiple cancers. Moreover, the GSEA unveiled that FTO was involved in the regulation of tumors and immune-related signaling pathways. In addition, several m6A related genes were implicated in the PPI network of FTO. Conclusion FTO was related to patients’ prognosis and tumor immune infiltrates in various cancers, and may serve as a novel and potential prognostic and immune biomarker in human pan-cancer.
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Affiliation(s)
- Chengwen Zhao
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Yonghui Liu
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Shaoqing Ju
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China.,Department of Public Health, Nantong University, Nantong, Jiangsu, People's Republic of China
| | - Xudong Wang
- Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, People's Republic of China.,Department of Public Health, Nantong University, Nantong, Jiangsu, People's Republic of China
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38
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Roudko V, Cimen Bozkus C, Greenbaum B, Lucas A, Samstein R, Bhardwaj N. Lynch Syndrome and MSI-H Cancers: From Mechanisms to "Off-The-Shelf" Cancer Vaccines. Front Immunol 2021; 12:757804. [PMID: 34630437 PMCID: PMC8498209 DOI: 10.3389/fimmu.2021.757804] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2021] [Accepted: 09/08/2021] [Indexed: 12/22/2022] Open
Abstract
Defective DNA mismatch repair (dMMR) is associated with many cancer types including colon, gastric, endometrial, ovarian, hepatobiliary tract, urinary tract, brain and skin cancers. Lynch syndrome - a hereditary cause of dMMR - confers increased lifetime risk of malignancy in different organs and tissues. These Lynch syndrome pathogenic alleles are widely present in humans at a 1:320 population frequency of a single allele and associated with an up to 80% risk of developing microsatellite unstable cancer (microsatellite instability - high, or MSI-H). Advanced MSI-H tumors can be effectively treated with checkpoint inhibitors (CPI), however, that has led to response rates of only 30-60% despite their high tumor mutational burden and favorable immune gene signatures in the tumor microenvironment (TME). We and others have characterized a subset of MSI-H associated highly recurrent frameshift mutations that yield shared immunogenic neoantigens. These frameshifts might serve as targets for off-the-shelf cancer vaccine designs. In this review we discuss the current state of research around MSI-H cancer vaccine development, its application to MSI-H and Lynch syndrome cancer patients and the utility of MSI-H as a biomarker for CPI therapy. We also summarize the tumor intrinsic mechanisms underlying the high occurrence rates of certain frameshifts in MSI-H. Finally, we provide an overview of pivotal clinical trials investigating MSI-H as a biomarker for CPI therapy and MSI-H vaccines. Overall, this review aims to inform the development of novel research paradigms and therapeutics.
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Affiliation(s)
- Vladimir Roudko
- Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Cansu Cimen Bozkus
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Benjamin Greenbaum
- Epidemiology and Biostatistics, Computational Oncology program, Memorial Sloan Kettering Cancer Center, New York, NY, United States.,Physiology, Biophysics & Systems Biology, Weill Cornell Medical College, New York, NY, United States
| | - Aimee Lucas
- Henry D. Janowitz Division of Gastroenterology, Samuel D. Bronfman Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, United States
| | - Robert Samstein
- Precision Immunology Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Department of Radiation Oncology, Mount Sinai Hospital, New York, NY, United States
| | - Nina Bhardwaj
- Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, United States.,Division of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
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39
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Development of New Cancer Treatment by Identifying and Focusing the Genetic Mutations or Altered Expression in Gynecologic Cancers. Genes (Basel) 2021; 12:genes12101593. [PMID: 34680987 PMCID: PMC8535522 DOI: 10.3390/genes12101593] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Revised: 10/05/2021] [Accepted: 10/07/2021] [Indexed: 12/29/2022] Open
Abstract
With the advent of next-generation sequencing (NGS), The Cancer Genome Atlas (TCGA) research network has given gynecologic cancers molecular classifications, which impacts clinical practice more and more. New cancer treatments that identify and target pathogenic abnormalities of genes have been in rapid development. The most prominent progress in gynecologic cancers is the clinical efficacy of poly(ADP-ribose) polymerase (PARP) inhibitors, which have shown breakthrough benefits in reducing hazard ratios (HRs) (HRs between 0.2 and 0.4) of progression or death from BRCA1/2 mutated ovarian cancer. Immune checkpoint inhibition is also promising in cancers that harbor mismatch repair deficiency (dMMR)/microsatellite instability (MSI). In this review, we focus on the druggable genetic alterations in gynecologic cancers by summarizing literature findings and completed and ongoing clinical trials.
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40
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Wu W, Liu Y, Zeng S, Han Y, Shen H. Intratumor heterogeneity: the hidden barrier to immunotherapy against MSI tumors from the perspective of IFN-γ signaling and tumor-infiltrating lymphocytes. J Hematol Oncol 2021; 14:160. [PMID: 34620200 PMCID: PMC8499512 DOI: 10.1186/s13045-021-01166-3] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2021] [Accepted: 09/07/2021] [Indexed: 12/15/2022] Open
Abstract
In this era of precision medicine, with the help of biomarkers, immunotherapy has significantly improved prognosis of many patients with malignant tumor. Deficient mismatch repair (dMMR)/microsatellite instability (MSI) status is used as a biomarker in clinical practice to predict favorable response to immunotherapy and prognosis. MSI is an important characteristic which facilitates mutation and improves the likelihood of a favorable response to immunotherapy. However, many patients with dMMR/MSI still respond poorly to immunotherapies, which partly results from intratumor heterogeneity propelled by dMMR/MSI. In this review, we discuss how dMMR/MSI facilitates mutations in tumor cells and generates intratumor heterogeneity, especially through type II interferon (IFN-γ) signaling and tumor-infiltrating lymphocytes (TILs). We discuss the mechanism of immunotherapy from the perspective of dMMR/MSI, molecular pathways and TILs, and we discuss how intratumor heterogeneity hinders the therapeutic effect of immunotherapy. Finally, we summarize present techniques and strategies to look at the tumor as a whole to design personalized regimes and achieve favorable prognosis.
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Affiliation(s)
- Wantao Wu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008
| | - Yihan Liu
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008
| | - Shan Zeng
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
| | - Ying Han
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
| | - Hong Shen
- Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- Key Laboratory for Molecular Radiation Oncology of Hunan Province, Xiangya Hospital, Central South University, Changsha, Hunan, People's Republic of China, 410008.
- National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, People's Republic of China.
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41
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Sensitive detection of microsatellite instability in tissues and liquid biopsies: Recent developments and updates. Comput Struct Biotechnol J 2021; 19:4931-4940. [PMID: 34527197 PMCID: PMC8433064 DOI: 10.1016/j.csbj.2021.08.037] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 08/23/2021] [Accepted: 08/24/2021] [Indexed: 12/16/2022] Open
Abstract
Microsatellite instability (MSI), a phenotype displayed as deletions/insertions of repetitive genomic sequences, has drawn great attention due to its application in cancer including diagnosis, prognosis and immunotherapy response prediction. Several methods have been developed for the detection of MSI, facilitating the MSI classification of cancer patients. In view of recent interest in minimally-invasive detection of MSI via liquid biopsy samples, which requires methods with high sensitivity to identify small fractions of altered DNA in the presence of large amount of wild type copies, sensitive MSI detection approaches are emerging. Here we review the available MSI detection methods and their detection limits and focus on recently developed next-generation-sequencing based approaches and bioinformatics algorithms available for MSI analysis in various cancer types.
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42
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Abstract
The rapid adoption of next-generation sequencing in clinical oncology has enabled the detection of molecular biomarkers shared between multiple tumor types. These pan-cancer biomarkers include sequence-altering mutations, copy number changes, gene rearrangements, and mutational signatures and have been demonstrated to predict response to targeted therapy. This article reviews issues surrounding current and emerging pan-cancer molecular biomarkers in clinical oncology: technological advances that enable the broad detection of cancer mutations across hundreds of genes, the spectrum of driver and passenger mutations derived from human cancer genomes, and implications for patient care now and in the near future.
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Affiliation(s)
- Fei Dong
- Department of Pathology, Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115, USA.
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43
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Rosenbaum JN, Berry AB, Church AJ, Crooks K, Gagan JR, López-Terrada D, Pfeifer JD, Rennert H, Schrijver I, Snow AN, Wu D, Ewalt MD. A Curriculum for Genomic Education of Molecular Genetic Pathology Fellows: A Report of the Association for Molecular Pathology Training and Education Committee. J Mol Diagn 2021; 23:1218-1240. [PMID: 34245921 DOI: 10.1016/j.jmoldx.2021.07.001] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2019] [Revised: 06/16/2021] [Accepted: 07/01/2021] [Indexed: 12/19/2022] Open
Abstract
Molecular genetic pathology (MGP) is a subspecialty of pathology and medical genetics and genomics. Genomic testing, which we define as that which generates large data sets and interrogates large segments of the genome in a single assay, is increasingly recognized as essential for optimal patient care through precision medicine. The most common genomic testing technologies in clinical laboratories are next-generation sequencing and microarray. It is essential to train in these methods and to consider the data generated in the context of the diagnosis, medical history, and other clinical findings of individual patients. Accordingly, updating the MGP fellowship curriculum to include genomics is timely, important, and challenging. At the completion of training, an MGP fellow should be capable of independently interpreting and signing out results of a wide range of genomic assays and, given the appropriate context and institutional support, of developing and validating new assays in compliance with applicable regulations. The Genomics Task Force of the MGP Program Directors, a working group of the Association for Molecular Pathology Training and Education Committee, has developed a genomics curriculum framework and recommendations specific to the MGP fellowship. These recommendations are presented for consideration and implementation by MGP fellowship programs with the understanding that MGP programs exist in a diversity of clinical practice environments with a spectrum of available resources.
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Affiliation(s)
- Jason N Rosenbaum
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Anna B Berry
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Swedish Cancer Institute and Institute of Systems Biology, Seattle, Washington
| | - Alanna J Church
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, Boston Children's Hospital, Boston, Massachusetts
| | - Kristy Crooks
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Jeffrey R Gagan
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas
| | - Dolores López-Terrada
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, Baylor College of Medicine, Houston, Texas
| | - John D Pfeifer
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, Washington University School of Medicine, St. Louis, Missouri
| | - Hanna Rennert
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, New York
| | - Iris Schrijver
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, Stanford University School of Medicine, Stanford, California
| | - Anthony N Snow
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, University of Iowa Hospitals and Clinics, Iowa City, Iowa
| | - David Wu
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Laboratory Medicine and Pathology, University of Washington, Seattle, Washington
| | - Mark D Ewalt
- Molecular Genetic Pathology Fellow Training in Genomics Task Force of the Training and Education Committee, Association for Molecular Pathology, Rockville, Maryland; Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Rizzo A, Ricci AD, Gadaleta-Caldarola G. MSI-H/dMMR and cancer immunotherapy: current state and future implications. EXPERT REVIEW OF PRECISION MEDICINE AND DRUG DEVELOPMENT 2021. [DOI: 10.1080/23808993.2021.1946391] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Alessandro Rizzo
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Medical Oncology Unit, “Mons. R. Dimiccoli” Hospital, Barletta, Italy
| | - Angela Dalia Ricci
- Medical Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italia
- Medical Oncology Unit, “Mons. R. Dimiccoli” Hospital, Barletta, Italy
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Westaby D, Viscuse PV, Ravilla R, de la Maza MDLDF, Hahn A, Sharp A, de Bono J, Aparicio A, Fleming MT. Beyond the Androgen Receptor: The Sequence, the Mutants, and New Avengers in the Treatment of Castrate-Resistant Metastatic Prostate Cancer. Am Soc Clin Oncol Educ Book 2021; 41:e190-e202. [PMID: 34061561 DOI: 10.1200/edbk_321209] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Targeting the androgen receptor by depriving testosterone with gonadotropin-releasing hormone agonists or antagonists, or surgical castration, has been the backbone of metastatic prostate cancer treatment. Although most prostate cancers initially respond to androgen deprivation, metastatic castration-resistant prostate cancer evolves into a heterogeneous disease with diverse drivers of progression and mechanisms of therapeutic resistance. Development of castrate resistance phenotype is associated with lethality despite the recent noteworthy strides gained via increase in therapeutic options. Identification of novel therapeutics to further improve survival and achieve durable responses in metastatic castration-resistant prostate cancer is a clinical necessity. In this review, we outline the existing avengers for treatment of metastatic castration-resistant prostate cancer by clinical presentation, placing into context the clinical state of the patient, such as burden of disease and symptoms. Doing so might aid in the ability to optimize the sequence of agents and allow for maximal exposure to life-prolonging therapeutics. Realizing the limitations of the androgen signaling inhibition, we explore the androgen-indifferent prostate cancer: the mutants. Classically, these subtypes have been associated with variant histology, but androgen-indifferent prostate cancer features are now frequently observed in association with heterogeneous morphologies, including double-negative prostate cancers, lacking both androgen receptor and neuroendocrine features, or clinicopathologic criteria, such as the aggressive variant prostate cancer criteria. The framework of new avengers against metastatic castration-resistant prostate cancer based on mechanism, including DNA repair, immune checkpoint inhibition, PTEN/PI3K/AKT pathway, prostate-specific membrane antigen targets, bispecific T-cell engagers, and radionuclide therapies, is summarized in this review.
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Affiliation(s)
- Daniel Westaby
- The Institute of Cancer Research and The Royal Marsden Hospital, London, United Kingdom
| | - Paul V Viscuse
- Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Rahul Ravilla
- US Oncology Research, New York Oncology Hematology, Albany, NY
| | | | - Andrew Hahn
- Division of Cancer Medicine, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Adam Sharp
- The Institute of Cancer Research and The Royal Marsden Hospital, London, United Kingdom
| | - Johann de Bono
- The Institute of Cancer Research and The Royal Marsden Hospital, London, United Kingdom
| | - Ana Aparicio
- Department of Genitourinary Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX
| | - Mark T Fleming
- US Oncology Research, Virginia Oncology Associates, Norfolk, VA
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46
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Gu P, Yang D, Zhu J, Zhang M, He X. Bioinformatics analysis identified hub genes in prostate cancer tumorigenesis and metastasis. MATHEMATICAL BIOSCIENCES AND ENGINEERING : MBE 2021; 18:3180-3196. [PMID: 34198380 DOI: 10.3934/mbe.2021158] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
OBJECTIVE Prostate cancer (PCa) is the most frequent cancer found in males worldwide, and its mortality rate is increasing every year. To discover key molecular changes in PCa development and metastasis, we analyzed microarray data of localized PCa, metastatic PCa and normal prostate tissue samples from clinical specimens. METHODS Gene expression profiling datasets of PCa were analyzed online. The DAVID was used to perform GO functional and KEGG pathway enrichment analyses. CytoHubba in Cytoscape software was applied to identify hub genes. Survival data were downloaded from GEPIA. Gene expression data were obtained from ONCOMINE and UALCAN. RESULTS We obtained 4 sets of differentially expressed genes (DEGs), DEGs 1: a comparison of the gene expression between 4 normal prostate and 5 localized PCa samples in GSE27616; DEGs 2: a comparison of the gene expression between 6 normal prostate and 7 localized PCa samples in GSE3325; DEGs 3: a comparison of the gene expression between 5 localized PCa and 4 metastatic PCa samples in GSE27616; DEGs 4: a comparison of the gene expression between 7 localized PCa and 6 metastatic PCa samples in GSE3325. A comparison of these 4 sets of genes revealed 51 overlapped genes. GO function analysis revealed enrichment of the 51 DEGs in functions related to the proteinaceous extracellular matrix and centrosome, protein homodimerization activity and chromatin binding were the main functions of these genes, which participated in regulating cell division, mitotic nuclear division, proteinaceous extracellular matrix, cell adhesion and apoptotic process. KEGG pathway analysis indicated that these identified DEGs were mainly enriched in progesterone-mediated oocyte maturation, oocyte meiosis and cell cycle. We defined the 16 genes with the highest degree of connectivity as the hub genes in the 51 overlapped DEGs. Cox regression revealed TOP2A, CCNB2, BUB1, CDK1 and EZH2 were related to Disease-free survival (DFS). The expression levels of the 5 genes were 2.232-, 1.786-, 2.303-, 1.699-, and 1.986-fold higher in PCa than the levels in normal tissues, respectively (P < 0.05). We obtained 20 hub genes from DEGs by the comparison of normal prostate tissue vs. localized cancer tissue. Among them, KIF20A, CDKN3, PBK and CDCA2, were expressed higher in PCa than in normal tissues, and were associated with the DFS of PCa patients. Meanwhile, we obtained 20 hub genes from DEGs by the comparison of localized cancer tissue vs. metastatic cancer tissue. Cox regression revealed PLK1, CCNA2 and CDC20, were associated with both the DFS and overall survival of PCa patients. CONCLUSIONS The results suggested that the functions of KIF20A, CDKN3, PBK and CDCA2 may contribute to PCa development and the functions of PLK1, CCNA2 and CDC20 may contribute to PCa metastasis. Meanwhile, the functions of TOP2A, CCNB2, BUB1, CDK1 and EZH2 may contribute to both PCa development and metastasis.
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Affiliation(s)
- Peng Gu
- Department of Urology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215000, China
- Department of Urology, Wuxi Xishan People's Hospital, 1128 Dacheng Road, Wuxi 214000, China
| | - Dongrong Yang
- Department of Urology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215000, China
| | - Jin Zhu
- Department of Urology, Second Affiliated Hospital of Soochow University, 1055 Sanxiang Road, Suzhou 215000, China
| | - Minhao Zhang
- Department of Urology, Wuxi Xishan People's Hospital, 1128 Dacheng Road, Wuxi 214000, China
| | - Xiaoliang He
- Department of Urology, Wuxi Xishan People's Hospital, 1128 Dacheng Road, Wuxi 214000, China
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Gilson P, Merlin JL, Harlé A. Detection of Microsatellite Instability: State of the Art and Future Applications in Circulating Tumour DNA (ctDNA). Cancers (Basel) 2021; 13:cancers13071491. [PMID: 33804907 PMCID: PMC8037825 DOI: 10.3390/cancers13071491] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2021] [Revised: 03/15/2021] [Accepted: 03/22/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary Microsatellite instability (MSI) is a molecular fingerprint for defects in the mismatch repair system (dMMR) and is associated with higher risks of cancers. MSI/dMMR tumours are characterized by the accumulation of mutations throughout the genome, and particularly in microsatellite (MS) DNA repeat sequences. MSI stands as a major biomarker for familial cancer risk assessment, cancer prognosis, and therapeutic choices. Standard-of-care classification of MSI/dMMR tumours is most frequently achieved using immunohistochemistry or PCR-based assay directed against a set of five MS regions. However, novel molecular methods based on tumour tissue or plasma samples have been developed and could enter in the future trends of MSI testing. Here, we provide insights into these emerging approaches and discuss their advantages and limitations. Abstract Microsatellite instability (MSI) is a molecular scar resulting from a defective mismatch repair system (dMMR) and associated with various malignancies. MSI tumours are characterized by the accumulation of mutations throughout the genome and particularly clustered in highly repetitive microsatellite (MS) regions. MSI/dMMR status is routinely assessed in solid tumours for the initial screening of Lynch syndrome, the evaluation of cancer prognosis, and treatment decision-making. Currently, pentaplex PCR-based methods and MMR immunohistochemistry on tumour tissue samples are the standard diagnostic methods for MSI/dMMR. Other tissue methods such as next-generation sequencing or real-time PCR-based systems have emerged and represent viable alternatives to standard MSI testing in specific settings. The evolution of the standard molecular techniques has offered the opportunity to extend MSI determination to liquid biopsy based on the analysis of cell-free DNA (cfDNA) in plasma. This review aims at synthetizing the standard and emerging techniques used on tumour tissue samples for MSI/dMMR determination. We also provide insights into the MSI molecular techniques compatible with liquid biopsy and the potential clinical consequences for patients with solid cancers.
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Affiliation(s)
- Pauline Gilson
- Correspondence: ; Tel.: +33-(0)3-8365-6035; Fax: +33-(0)3-8365-6152
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Patient-derived xenografts and organoids model therapy response in prostate cancer. Nat Commun 2021; 12:1117. [PMID: 33602919 PMCID: PMC7892572 DOI: 10.1038/s41467-021-21300-6] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2020] [Accepted: 01/19/2021] [Indexed: 02/08/2023] Open
Abstract
Therapy resistance and metastatic processes in prostate cancer (PCa) remain undefined, due to lack of experimental models that mimic different disease stages. We describe an androgen-dependent PCa patient-derived xenograft (PDX) model from treatment-naïve, soft tissue metastasis (PNPCa). RNA and whole-exome sequencing of the PDX tissue and organoids confirmed transcriptomic and genomic similarity to primary tumor. PNPCa harbors BRCA2 and CHD1 somatic mutations, shows an SPOP/FOXA1-like transcriptomic signature and microsatellite instability, which occurs in 3% of advanced PCa and has never been modeled in vivo. Comparison of the treatment-naïve PNPCa with additional metastatic PDXs (BM18, LAPC9), in a medium-throughput organoid screen of FDA-approved compounds, revealed differential drug sensitivities. Multikinase inhibitors (ponatinib, sunitinib, sorafenib) were broadly effective on all PDX- and patient-derived organoids from advanced cases with acquired resistance to standard-of-care compounds. This proof-of-principle study may provide a preclinical tool to screen drug responses to standard-of-care and newly identified, repurposed compounds.
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Zhu M, Jin Z, Hubbard JM. Management of Non-Colorectal Digestive Cancers with Microsatellite Instability. Cancers (Basel) 2021; 13:651. [PMID: 33561950 PMCID: PMC7915546 DOI: 10.3390/cancers13040651] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 01/26/2021] [Accepted: 02/03/2021] [Indexed: 02/08/2023] Open
Abstract
Microsatellite instability (MSI) is a hallmark of genetic predisposition to DNA damage. It arises from either germline or somatic events leading to impaired function of the mismatch repair system. It can be detected via genetic sequencing or immunohistochemistry with relatively high concordance rates. The presence of MSI in a tumor reflects a high neoantigen load and predicts favorable treatment response to immune checkpoint inhibitors (ICIs). In gastrointestinal cancers, MSI is a predictive biomarker for ICIs with potential prognostic impact but its clinical utility varies widely depending on tumor type. This may be explained by the complexity of tumor microenvironment as highlighted by recent translational studies. In this review, we will discuss the predictive and prognostic value of MSI status in non-colorectal cancers of the digestive system, important clinical trials involving ICIs and potential strategies to overcome resistance to immunotherapy.
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Affiliation(s)
- Mojun Zhu
- Department of Medical Oncology, Mayo Clinic, Rochester, MN 55905, USA; (Z.J.); (J.M.H.)
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50
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Carneiro BA, Lotan TL, de Souza A, Aggarwal R. Emerging Subtypes and New Treatments for Castration-Resistant Prostate Cancer. Am Soc Clin Oncol Educ Book 2021; 40:e319-e332. [PMID: 32479115 DOI: 10.1200/edbk_100025] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/29/2023]
Abstract
Genomic characterization of metastatic castration-resistant prostate cancer (mCRPC) has been remodeling the treatment landscape of this disease in the past decade. The emergence of molecularly defined subsets of mCRPC is altering the treatment paradigm from therapeutics with nonspecific activity across the spectrum, including androgen receptor (AR)-directed treatments, docetaxel, and cabazitaxel, to targeted approaches directed at molecular subsets of disease. The meaningful benefit of PARP inhibitors in mCRPC carrying mutations in DNA repair genes demonstrated in a phase III trial epitomizes this transition in the treatment paradigm of mCRPC and brings new challenges related to how to sequence and integrate the targeted therapies on top of the treatments with broad activity in all mCRPC. To enable and sustain the advance of precision oncology in the management of mCRPC, genomic characterization is required, including somatic and germline testing, for all patients with the ultimate goal of longitudinal molecular profiling guiding treatment decisions and sequential treatments of this lethal disease. This article reviews the emerging molecular subtypes of mCRPC that are driving the evolution of mCRPC treatment.
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Affiliation(s)
- Benedito A Carneiro
- Warren Alpert Medical School, Brown University, Providence, RI.,Lifespan Cancer Institute, Providence, RI
| | - Tamara L Lotan
- Department of Pathology, Johns Hopkins University, Baltimore, MD
| | - Andre de Souza
- Warren Alpert Medical School, Brown University, Providence, RI.,Lifespan Cancer Institute, Providence, RI
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