Concurrent RB1 loss and BRCA -deficiency predicts enhanced immunological response and long-term survival in tubo-ovarian high-grade serous carcinoma.

Autor: Saner FAM; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Department of Obstetrics and Gynecology, Bern University Hospital and University of Bern, Bern, Switzerland., Takahashi K; Peter MacCallum Cancer Centre, Melbourne, Victoria, 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, New South Wales, Australia.; Skin Cancer and Ageing Lab, Cancer Research United Kingdom Manchester Institute, The University of Manchester, Manchester, UK., Pandey A; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Ariyaratne D; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Zwimpfer TA; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Meagher NS; School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.; The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia., Fereday S; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Twomey L; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Pishas KI; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Hoang T; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Bolithon A; School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia., Traficante N; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Alsop K; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Christie EL; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Kang EY; Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada., Nelson GS; Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Ghatage P; Department of Oncology, Division of Gynecologic Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada., Lee CH; Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada., Riggan MJ; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA., Alsop J; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., 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, New South Wales, Australia.; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.; The University of Sydney, Sydney, New South Wales, Australia., Brand AH; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.; The University of Sydney, Sydney, New South Wales, Australia., Brooks-Wilson A; Canada's Michael Smith Genome Sciences Centre, BC Cancer, Vancouver, BC, Canada., Carney ME; Department of Obstetrics and Gynecology, John A. Burns School of Medicine, University of Hawaii, Honolulu, HI, USA., Coulson P; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK., Courtney-Brooks M; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Cushing-Haugen KL; Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA., 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, UK., Elishaev E; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., 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, CA, USA., Gentry-Maharaj A; MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK.; Department of Women's Cancer, Elizabeth Garrett Anderson Institute for Women's Health, University College London, London, UK., Blake Gilks C; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada., Harnett PR; The University of Sydney, Sydney, New South Wales, Australia.; Crown Princess Mary Cancer Centre, Westmead Hospital, Sydney, New South Wales, Australia., Harris HR; Program in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Center, Seattle, WA, USA.; Department of Epidemiology, University of Washington, Seattle, WA, USA., 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, Victoria, Australia., Hernandez BY; University of Hawaii Cancer Center, Honolulu, HI, USA., 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, UK., Jones ME; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK., Kaufmann SH; Division of Oncology Research, Department of Oncology, Mayo Clinic, Rochester, MN, USA., Kennedy CJ; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.; The University of Sydney, Sydney, New South Wales, 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, AB, 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, BC, Canada., Lener M; International Hereditary Cancer Center, Department of Genetics and Pathology, Pomeranian Medical University in Szczecin, Szczecin, Poland., Lester J; David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA., 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; David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA., Ruebner M; Department of Gynecology and Obstetrics, Comprehensive Cancer Center Erlangen-EMN, Friedrich-Alexander University Erlangen-Nuremberg, University Hospital Erlangen, Erlangen, Germany., Schoemaker MJ; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Shah M; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK., Sharma R; Tissue Pathology and Diagnostic Oncology, Westmead Hospital, Sydney, New South Wales, Australia., Sherman ME; Department of Health Sciences Research, Mayo Clinic, Jacksonville, FL, USA., Shvetsov YB; University of Hawaii Cancer Center, Honolulu, HI, USA., Singh N; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, BC, Canada., Rinda Soong T; Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Steed H; Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.; Section of Gynecologic Oncology Surgery, North Zone, Alberta Health Services, Edmonton, Alberta, Canada., Sukumvanich P; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Talhouk A; British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada.; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada., Taylor SE; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA., Vierkant RA; Department of Quantitative Health Sciences, Division of Clinical Trials and Biostatistics, Mayo Clinic, Rochester, MN, USA., Wang C; Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA., Widschwendter M; EUTOPS Institute, University of Innsbruck, Innsbruck, Austria., Wilkens LR; University of Hawaii Cancer Center, Honolulu, HI, USA., Winham SJ; Department of Quantitative Health Sciences, Division of Computational Biology, Mayo Clinic, Rochester, MN, USA., Anglesio MS; British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada.; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada., Berchuck A; Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Duke University Medical Center, Durham, NC, USA., Brenton JD; Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK., Campbell I; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Cook LS; Epidemiology, School of Public Health, University of Colorado, Aurora, CO, USA.; Community Health Sciences, University of Calgary, Calgary, AB, Canada., Doherty JA; Huntsman Cancer Institute, Department of Population Health Sciences, University of Utah, Salt Lake City, UT, USA., 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, Oslo, Norway., Goodman MT; Cancer Prevention and Control Program, Cedars-Sinai Cancer, Cedars-Sinai Medical Center, Los Angeles, CA, USA., 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, BC, Canada.; British Columbia's Gynecological Cancer Research Team (OVCARE), University of British Columbia, BC Cancer, and Vancouver General Hospital, Vancouver, BC, Canada.; Department of Obstetrics and Gynecology, University of British Columbia, Vancouver, BC, Canada.; Department of Molecular Oncology, BC Cancer Research Centre, Vancouver, BC, Canada., Karlan BY; David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles, Los Angeles, CA, USA., Kelemen LE; Division of Acute Disease Epidemiology, South Carolina Department of Health & Environmental Control, Columbia, SC, USA., Menon U; MRC Clinical Trials Unit, Institute of Clinical Trials and Methodology, University College London, London, UK., Modugno F; Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.; Department of Epidemiology, University of Pittsburgh School of Public Health, Pittsburgh, PA, USA.; Women's Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center, Pittsburgh, PA, USA., Pharoah PDP; Centre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge, Cambridge, UK.; Department of Computational Biomedicine, Cedars-Sinai Medical Center, West Hollywood, CA, USA.; Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of Cambridge, Cambridge, UK., Schildkraut JM; Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA, USA., Sundfeldt K; Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenburg, Sweden., Swerdlow AJ; Division of Genetics and Epidemiology, The Institute of Cancer Research, London, UK.; Division of Breast Cancer Research, The Institute of Cancer Research, London, UK., Goode EL; Department of Quantitative Health Sciences, Division of Epidemiology, Mayo Clinic, Rochester, MN, USA., DeFazio A; The Daffodil Centre, The University of Sydney, a joint venture with Cancer Council NSW, Sydney, New South Wales, Australia.; Centre for Cancer Research, The Westmead Institute for Medical Research, Sydney, New South Wales, Australia.; Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales, Australia.; The University of Sydney, Sydney, New South Wales, Australia., Köbel M; Department of Pathology and Laboratory Medicine, University of Calgary, Foothills Medical Center, Calgary, AB, Canada., Ramus SJ; School of Clinical Medicine, UNSW Medicine and Health, University of NSW Sydney, Sydney, New South Wales, Australia.; Adult Cancer Program, Lowy Cancer Research Centre, University of NSW Sydney, Sydney, New South Wales, Australia., Bowtell DDL; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia., Garsed DW; Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, Victoria, Australia.
Jazyk: angličtina
Zdroj: MedRxiv : the preprint server for health sciences [medRxiv] 2023 Nov 10. Date of Electronic Publication: 2023 Nov 10.
DOI: 10.1101/2023.11.09.23298321
Abstrakt: Background: Somatic loss of the tumour suppressor RB1 is a common event in tubo-ovarian high-grade serous carcinoma (HGSC), which frequently co-occurs with alterations in homologous recombination DNA repair genes including BRCA1 and BRCA2 ( BRCA ). We examined whether tumour expression of RB1 was associated with survival across ovarian cancer histotypes (HGSC, endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous carcinoma (LGSC)), and how co-occurrence of germline BRCA pathogenic variants and RB1 loss influences long-term survival in a large series of HGSC.
Patients and Methods: RB1 protein expression patterns were classified by immunohistochemistry in epithelial ovarian carcinomas of 7436 patients from 20 studies participating in the Ovarian Tumor Tissue Analysis consortium and assessed for associations with overall survival (OS), accounting for patient age at diagnosis and FIGO stage. We examined RB1 expression and germline BRCA status in a subset of 1134 HGSC, and related genotype to survival, tumour infiltrating CD8+ lymphocyte counts and transcriptomic subtypes. Using CRISPR-Cas9, we deleted RB1 in HGSC cell lines with and without BRCA1 mutations to model co-loss with treatment response. We also performed genomic analyses on 126 primary HGSC to explore the molecular characteristics of concurrent homologous recombination deficiency and RB1 loss.
Results: RB1 protein loss was most frequent in HGSC (16.4%) and was highly correlated with RB1 mRNA expression. RB1 loss was associated with longer OS in HGSC (hazard ratio [HR] 0.74, 95% confidence interval [CI] 0.66-0.83, P = 6.8 ×10 -7 ), but with poorer prognosis in ENOC (HR 2.17, 95% CI 1.17-4.03, P = 0.0140). Germline BRCA mutations and RB1 loss co-occurred in HGSC ( P < 0.0001). Patients with both RB1 loss and germline BRCA mutations had a superior OS (HR 0.38, 95% CI 0.25-0.58, P = 5.2 ×10 -6 ) compared to patients with either alteration alone, and their median OS was three times longer than non-carriers whose tumours retained RB1 expression (9.3 years vs. 3.1 years). Enhanced sensitivity to cisplatin ( P < 0.01) and paclitaxel ( P < 0.05) was seen in BRCA1 mutated cell lines with RB1 knockout. Among 126 patients with whole-genome and transcriptome sequence data, combined RB1 loss and genomic evidence of homologous recombination deficiency was correlated with transcriptional markers of enhanced interferon response, cell cycle deregulation, and reduced epithelial-mesenchymal transition in primary HGSC. CD8+ lymphocytes were most prevalent in BRCA -deficient HGSC with co-loss of RB1 .
Conclusions: Co-occurrence of RB1 loss and BRCA mutation was associated with exceptionally long survival in patients with HGSC, potentially due to better treatment response and immune stimulation.
Competing Interests: COMPETING INTERESTS DDLB is an Exo Therapeutics advisor and has received research grant funding from AstraZeneca, Genentech-Roche and BeiGene for unrelated work. SF, NT, KA, and ADeF received grant funding from AstraZeneca for unrelated work. AGM and UM report funded research collaborations for unrelated work with industry: Intelligent Lab on Fiber, RNA Guardian, Micronoma and Mercy BioAnalytics. UM had stock ownership (2011–2021) awarded by University College London (UCL) in Abcodia, which held the licence for the Risk of Ovarian Cancer Algorithm (ROCA). UM reports research collaboration contracts with Cambridge University and QIMR Berghofer Medical Research Institute. UM holds patent number EP10178345.4 for Breast Cancer Diagnostics. UM is a member of Tina’s Wish Scientific Advisory Board (USA) and Research Advisory Panel, Yorkshire Cancer Research (UK). The remaining authors declared no conflicts of interest.
Databáze: MEDLINE
Externí odkaz: