Concurrent RB1 Loss and BRCA Deficiency Predicts Enhanced Immunologic Response and Long-term Survival in Tubo-ovarian High-grade Serous Carcinoma.

Autor:	Saner FAM; Peter MacCallum Cancer Centre, Melbourne, Australia.; Department of Obstetrics and Gynecology, Bern University Hospital and University of Bern, Bern, Switzerland., Takahashi K; Peter MacCallum Cancer Centre, Melbourne, Australia.; Department of Obstetrics and Gynecology, The Jikei University School of Medicine, Tokyo, Japan., Budden T; School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, Australia.; Skin Cancer and Ageing Lab, Cancer Research United Kingdom Manchester Institute, The University of Manchester, Manchester, United Kingdom., Pandey A; Peter MacCallum Cancer Centre, Melbourne, Australia., Ariyaratne D; Peter MacCallum Cancer Centre, Melbourne, Australia., Zwimpfer TA; Peter MacCallum Cancer Centre, Melbourne, Australia., Meagher NS; School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, Australia.; The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council New South Wales, Sydney, Australia., Fereday S; Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia., Twomey L; Peter MacCallum Cancer Centre, Melbourne, Australia., Pishas KI; Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia., Hoang T; Peter MacCallum Cancer Centre, Melbourne, Australia., Bolithon A; School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, Australia.; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, Australia., Traficante N; Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia., Alsop K; Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia., Christie EL; Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia., Kang EY; Department of Pathology and Laboratory Medicine, Foothills Medical Center, University of Calgary, Calgary, Canada., Nelson GS; Division of Gynecologic Oncology, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Canada., Ghatage P; Division of Gynecologic Oncology, Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, Canada., Lee CH; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Canada., Riggan MJ; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina., Alsop J; Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom., Beckmann MW; Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany., Boros J; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia.; Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.; The University of Sydney, Sydney, Australia., Brand AH; Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.; The University of Sydney, Sydney, Australia., Brooks-Wilson A; Canada's Michael Smith Genome Sciences Centre, Vancouver, Canada., Carney ME; Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii., Coulson P; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom., Courtney-Brooks M; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Cushing-Haugen KL; Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington., Cybulski C; Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland., El-Bahrawy MA; Department of Metabolism, Digestion and Reproduction, Imperial College London, Hammersmith Hospital, London, United Kingdom., Elishaev E; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Erber R; Institute of Pathology, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany., Gayther SA; Center for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical Center, Los Angeles, California., Gentry-Maharaj A; MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom.; Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, United Kingdom., Gilks CB; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada., Harnett PR; The University of Sydney, Sydney, Australia.; Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, Australia., Harris HR; Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, Washington.; Department of Epidemiology, University of Washington, Seattle, Washington., Hartmann A; Institute of Pathology, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany., Hein A; Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany., Hendley J; Peter MacCallum Cancer Centre, Melbourne, Australia., Hernandez BY; University of Hawaii Cancer Center, Honolulu, Hawaii., Jakubowska A; Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland.; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland., Jimenez-Linan M; Department of Histopathology, Addenbrooke's Hospital, Cambridge, United Kingdom., Jones ME; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom., Kaufmann SH; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, Minnesota., Kennedy CJ; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia.; Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.; The University of Sydney, Sydney, Australia., Kluz T; Department of Gynecology and Obstetrics, Gynecology Oncology and Obstetrics, Institute of Medical Sciences, Medical College of Rzeszow University, Rzeszów, Poland., Koziak JM; Alberta Health Services-Cancer Care, Calgary, Canada., Kristjansdottir B; Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden., Le ND; Cancer Control Research, BC Cancer Agency, Vancouver, Canada., Lener M; Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University in Szczecin, Szczecin, Poland., Lester J; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California., Lubiński J; Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland., Mateoiu C; Department of Pathology, University of Gothenburg, Gothenburg, Sweden., Orsulic S; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California., Ruebner M; Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany., Schoemaker MJ; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom., Shah M; Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom., Sharma R; Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, Australia., Sherman ME; Department of Health Sciences Research, Mayo Clinic, Jacksonville, Florida., Shvetsov YB; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland., Soong TR; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Steed H; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Canada.; Section of Gynecologic Oncology Surgery, North Zone, Alberta Health Services, Edmonton, Canada., Sukumvanich P; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Talhouk A; British Columbia's Gynecological Cancer Research Team (OVCARE), BC Cancer, and Vancouver General Hospital, University of British Columbia, Vancouver, Canada.; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada., Taylor SE; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania., Vierkant RA; Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, Minnesota., Wang C; Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota., Widschwendter M; EUTOPS Institute, University of Innsbruck, Innsbruck, Austria., Wilkens LR; Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical University, Szczecin, Poland., Winham SJ; Division of Computational Biology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota., Anglesio MS; British Columbia's Gynecological Cancer Research Team (OVCARE), BC Cancer, and Vancouver General Hospital, University of British Columbia, Vancouver, Canada.; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada., Berchuck A; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, Duke University Medical Center, Durham, North Carolina., Brenton JD; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, United Kingdom., Campbell I; Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia., Cook LS; Department of Epidemiology, School of Public Health, University of Colorado, Aurora, Colorado.; Community Health Sciences, University of Calgary, Calgary, Canada., Doherty JA; Department of Population Health Sciences, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah., Fasching PA; Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany., Fortner RT; Division of Cancer Epidemiology, German Cancer Research Center (DKFZ), Heidelberg, Germany.; Department of Research, Cancer Registry of Norway, Norwegian Institute of Public Health, Oslo, Norway., Goodman MT; Cancer Prevention and Control Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, California., Gronwald J; Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, Szczecin, Poland., Huntsman DG; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.; British Columbia's Gynecological Cancer Research Team (OVCARE), BC Cancer, and Vancouver General Hospital, University of British Columbia, Vancouver, Canada.; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, Canada.; Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, Canada., Karlan BY; Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, California., Kelemen LE; Division of Acute Disease Epidemiology, South Carolina Department of Health & Environmental Control, Columbia, South Carolina., Menon U; MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, United Kingdom., Modugno F; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania.; Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, Pennsylvania.; Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, Pennsylvania., Pharoah PDP; Department of Oncology, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, United Kingdom.; Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, California.; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, United Kingdom., Schildkraut JM; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, Georgia., Sundfeldt K; Cancer Control Research, BC Cancer Agency, Vancouver, Canada., Swerdlow AJ; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, United Kingdom.; Division of Breast Cancer Research, The Institute of Cancer Research, London, United Kingdom., Goode EL; Division of Epidemiology, Department of Quantitative Health Sciences, Mayo Clinic, Rochester, Minnesota., DeFazio A; The Daffodil Centre, The University of Sydney, A Joint Venture with Cancer Council New South Wales, Sydney, Australia.; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, Australia.; Department of Gynaecological Oncology, Westmead Hospital, Sydney, Australia.; The University of Sydney, Sydney, Australia., Köbel M; Department of Pathology and Laboratory Medicine, Foothills Medical Center, University of Calgary, Calgary, Canada., Ramus SJ; School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, Australia.; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, Australia., Bowtell DDL; Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia., Garsed DW; Peter MacCallum Cancer Centre, Melbourne, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Australia.
Jazyk:	angličtina
Zdroj:	Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2024 Aug 15; Vol. 30 (16), pp. 3481-3498.
DOI:	10.1158/1078-0432.CCR-23-3552
Abstrakt:	Purpose: The purpose of this study was to evaluate RB1 expression and survival across ovarian carcinoma histotypes and how co-occurrence of BRCA1 or BRCA2 (BRCA) alterations and RB1 loss influences survival in tubo-ovarian high-grade serous carcinoma (HGSC). Experimental Design: RB1 protein expression was classified by immunohistochemistry in ovarian carcinomas of 7,436 patients from the Ovarian Tumor Tissue Analysis consortium. We examined RB1 expression and germline BRCA status in a subset of 1,134 HGSC, and related genotype to overall survival (OS), tumor-infiltrating CD8+ lymphocytes, and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cells with and without BRCA1 alterations to model co-loss with treatment response. We performed whole-genome and transcriptome data analyses on 126 patients with primary HGSC to characterize tumors with concurrent BRCA deficiency and RB1 loss. Results: RB1 loss was associated with longer OS in HGSC but with poorer prognosis in endometrioid ovarian carcinoma. Patients with HGSC harboring both RB1 loss and pathogenic germline BRCA variants had superior OS compared with patients with either alteration alone, and their median OS was three times longer than those without pathogenic BRCA variants and retained RB1 expression (9.3 vs. 3.1 years). Enhanced sensitivity to cisplatin and paclitaxel was seen in BRCA1-altered cells with RB1 knockout. Combined RB1 loss and BRCA deficiency correlated with transcriptional markers of enhanced IFN response, cell-cycle deregulation, and reduced epithelial-mesenchymal transition. CD8+ lymphocytes were most prevalent in BRCA-deficient HGSC with co-loss of RB1. Conclusions: Co-occurrence of RB1 loss and BRCA deficiency was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation. (©2024 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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