Population based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high grade serous ovarian cancer
Population based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high grade serous ovarian cancer
Abstract PurposeThe known EOC susceptibility genes account for less than 50% of the heritable risk of ovarian cancer suggesting other susceptibility genes exist. The aim of this study was to evaluate the contribution to ovarian cancer susceptibility of rare deleterious germline variants in a set of candidate genes. MethodsWe sequenced the coding region of 54 candidate genes in 6385 invasive EOC cases and 6115 controls of broad European ancestry. Genes with an increased frequency of putative deleterious variants in cases verses controls were further examined in an independent set of 14,146 EOC cases and 28,661 controls from the ovarian cancer association consortium and the UK Biobank. For each gene, we estimated the EOC risks and evaluated associations between germline variant status and clinical characteristics. ResultsThe odds ratios (OR) associated for high-grade serous ovarian cancer were 3.01 for PALB2 (95% CI 1.59 – 5.68; P = 0.00068), 1.99 for POLK (95% CI 1.15 – 3.43; P = 0.014), and 4.07 for SLX4 (95% CI 1.34-12.4; P = 0.013). Deleterious mutations in FBXO10 were associated with a reduced risk of disease (OR 0.27, 95% CI 0.07 ?1.00, P=0.049). However, based on the Bayes false discovery probability, only the association for PALB2 in high-grade serous ovarian cancer is likely to represent a true positive. ConclusionsWe have found strong evidence that carriers of PALB2 deleterious mutations are at increased risk of high-grade serous ovarian cancer. Whether the magnitude of risk is sufficiently high to warrant the inclusion of PALB2 in cancer gene panels for ovarian cancer risk testing is unclear; much larger sample sizes will be needed to provide sufficiently precise estimates for clinical counselling.
D?rk Thilo、Bogdanova Natalia V.、Moysich Kirsten B.、Ness Roberta B.、Karlan Beth Y.、Song Honglin、Chenevix-Trench Georgia、Bowtell David D、Jensen Allan、Campbell Ian、Winham Stacey J.、Hildebrandt Michelle A.T.、Huff Chad、Li Donghui、Permuth Jennifer B.、Berchuck Andrew、Jakubowska Anna、Goranova Teodora、Hosking Karen、Van Oudenhove Elke、Harris Holly R.、Rossing Mary Anne、Harrington Patricia A.、Chan Isaac、Pearce Celeste L.、Ramus Susan J.、Gayther Simon A.、Brenton James D.、OPAL Study Group、Pujana Miquel Angel、Kennedy Catherine J.、Webb Penelope M.、Gronwald Jacek、Menon Usha、Pharoah Paul D.P.、Wu Anna H.、Alsop Jennifer、Cunningham Julie M.、Tyrer Jonathan P.、Schildkraut Joellen M.、Levine Douglas A.、AOCS Group、H?gdall Estrid、Lester Jenny、Lazaro Conxi、D¨1rst Matthias、Dicks Ed、Traficante Nadia、Doherty Jennifer Anne、Kjaer Susanne K.、Intermaggio Maria、de Fazio Anna、Vierkant Robert A.、Yu Yao、Riggan Marjorie J.、Cybulski Cezary、Wu Xifeng、Piskorz Anna、Goode Ellen L.、Lubi¨?ski Jan、Odunsi Kunle、Modugno Francesmary
Gynaecology Research Unit, Hannover Medical SchoolGynaecology Research Unit, Hannover Medical School||Department of Radiation Oncology, Hannover Medical School||N.N. Alexandrov Research Institute of Oncology and Medical RadiologyDivision of Cancer Prevention and Control, Roswell Park Cancer InstituteSchool of Public Health, University of Texas Health Science Center at Houston (UTHealth)David Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles||Women?ˉs Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterCentre for Cancer Genetic Epidemiology, Department of Oncology, University of CambridgeDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research InstituteDept of Research, Cancer Genomics and Genetics and Women?ˉs Cancer Programs, Peter MacCallum Cancer Center||Sir Peter MacCallum Department of Oncology, The University of MelbourneDepartment of Virus, Lifestyle and Genes, Danish Cancer Society Research CenterResearch Department, Peter MacCallum Cancer Center||Sir Peter MacCallum Department of Oncology, The University of MelbourneDepartment of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo ClinicDepartment of Epidemiology, University of Texas MD Anderson Cancer CenterDepartment of Epidemiology, University of Texas MD Anderson Cancer CenterDepartment of Epidemiology, University of Texas MD Anderson Cancer CenterDepartment of Cancer Epidemiology, Moffitt Cancer CenterDepartment of Gynecologic Oncology, Duke University HospitalDepartment of Genetics and Pathology, Pomeranian Medical University||Independent Laboratory of Molecular Biology and Genetic Diagnostics, Pomeranian Medical UniversityCancer Research UK Cambridge Institute, University of CambridgeDepartment of Oncology, University of CambridgeGynecologic Oncology, Laura and Isaac Perlmutter Cancer Center, NYU Langone Medical CenterProgram in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center||Department of Epidemiology, University of WashingtonProgram in Epidemiology, Division of Public Health Sciences, Fred Hutchinson Cancer Research Center||Department of Epidemiology, University of WashingtonCentre for Cancer Genetic Epidemiology, Department of Oncology, University of CambridgeSchool of Women?ˉs and Children?ˉs Health, Faculty of Medicine, University of NSW SydneyDepartment of Epidemiology, University of Michigan School of Public Health||Department of Preventive Medicine, Keck School of Medicine, University of Southern California Norris Comprehensive Cancer CenterSchool of Women?ˉs and Children?ˉs Health, Faculty of Medicine, University of NSW Sydney||The Kinghorn Cancer Centre, Garvan Institute of Medical Research. SydneyCenter for Bioinformatics and Functional Genomics and the Cedars Sinai Genomics Core, Cedars-Sinai Medical CenterCancer Research UK Cambridge Institute, University of CambridgePopulation Health Department, QIMR Berghofer Medical Research InstituteTranslational Research Laboratory, IDIBELL (Bellvitge Biomedical Research Institute),Catalan Institute of Oncology, CIBERONCCentre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney||Department of Gynaecological Oncology, Westmead HospitalPopulation Health Department, QIMR Berghofer Medical Research InstituteDepartment of Genetics and Pathology, Pomeranian Medical UniversityMRC Clinical Trials Unit at UCL, Institute of Clinical Trials & Methodology, University College LondonCentre for Cancer Genetic Epidemiology, Department of Oncology, University of Cambridge||Centre for Cancer Genetic Epidemiology, Department of Public Health and Primary Care, University of CambridgeDepartment of Preventive Medicine, Keck School of Medicine, University of Southern CaliforniaCentre for Cancer Genetic Epidemiology, Department of Oncology, University of CambridgeDepartment of Laboratory Medicine and Pathology, Mayo ClinicCentre for Cancer Genetic Epidemiology, Department of Oncology, University of CambridgeDepartment of Public Health Sciences, University of VirginiaGynecology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center||Gynecologic Oncology, Laura and Isaac Pearlmutter Cancer Center, NYU Langone Medical CenterDepartment of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute||Research Department, Peter MacCallum Cancer CenterDepartment of Virus, Lifestyle and Genes, Danish Cancer Society Research Center||Molecular Unit, Department of Pathology, Herlev Hospital, University of CopenhagenDavid Geffen School of Medicine, Department of Obstetrics and Gynecology, University of California at Los Angeles||Women?ˉs Cancer Program at the Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical CenterHereditary Cancer Program, ONCOBELL-IDIBELL-IDIBGI-IGTP, Catalan Institute of Oncology, CIBERONCDepartment of Gynaecology, Jena University Hospital - Friedrich Schiller UniversityCentre for Cancer Genetic Epidemiology, Department of Oncology, University of CambridgeSir Peter MacCallum Department of Oncology, The University of MelbourneHuntsman Cancer Institute, Department of Population Health Sciences, University of UtahDepartment of Virus, Lifestyle and Genes, Danish Cancer Society Research Center||Department of Gynaecology, Rigshospitalet, University of CopenhagenSchool of Women?ˉs and Children?ˉs Health, Faculty of Medicine, University of NSW Sydney||The Kinghorn Cancer Centre, Garvan Institute of Medical Research. SydneyCentre for Cancer Research, The Westmead Institute for Medical Research, The University of Sydney||Department of Gynaecological Oncology, Westmead HospitalDepartment of Health Science Research, Division of Biomedical Statistics and Informatics, Mayo ClinicDepartment of Epidemiology, University of Texas MD Anderson Cancer CenterDepartment of Gynecologic Oncology, Duke University HospitalDepartment of Genetics and Pathology, Pomeranian Medical UniversityDepartment of Epidemiology, University of Texas MD Anderson Cancer CenterCancer Research UK Cambridge Institute, University of CambridgeDepartment of Health Science Research, Division of Epidemiology, Mayo ClinicDepartment of Genetics and Pathology, Pomeranian Medical UniversityDepartment of Gynecologic Oncology, Roswell Park Cancer InstituteWomens Cancer Research Center, Magee-Womens Research Institute and Hillman Cancer Center||Division of Gynecologic Oncology, Department of Obstetrics, Gynecology and Reproductive Sciences, University of Pittsburgh School of Medicine
肿瘤学医学研究方法基础医学
D?rk Thilo,Bogdanova Natalia V.,Moysich Kirsten B.,Ness Roberta B.,Karlan Beth Y.,Song Honglin,Chenevix-Trench Georgia,Bowtell David D,Jensen Allan,Campbell Ian,Winham Stacey J.,Hildebrandt Michelle A.T.,Huff Chad,Li Donghui,Permuth Jennifer B.,Berchuck Andrew,Jakubowska Anna,Goranova Teodora,Hosking Karen,Van Oudenhove Elke,Harris Holly R.,Rossing Mary Anne,Harrington Patricia A.,Chan Isaac,Pearce Celeste L.,Ramus Susan J.,Gayther Simon A.,Brenton James D.,OPAL Study Group,Pujana Miquel Angel,Kennedy Catherine J.,Webb Penelope M.,Gronwald Jacek,Menon Usha,Pharoah Paul D.P.,Wu Anna H.,Alsop Jennifer,Cunningham Julie M.,Tyrer Jonathan P.,Schildkraut Joellen M.,Levine Douglas A.,AOCS Group,H?gdall Estrid,Lester Jenny,Lazaro Conxi,D¨1rst Matthias,Dicks Ed,Traficante Nadia,Doherty Jennifer Anne,Kjaer Susanne K.,Intermaggio Maria,de Fazio Anna,Vierkant Robert A.,Yu Yao,Riggan Marjorie J.,Cybulski Cezary,Wu Xifeng,Piskorz Anna,Goode Ellen L.,Lubi¨?ski Jan,Odunsi Kunle,Modugno Francesmary.Population based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high grade serous ovarian cancer[EB/OL].(2025-03-28)[2025-06-15].https://www.medrxiv.org/content/10.1101/19011924.点此复制
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