Rare, germline loss-of-function variants in a handful of DNA repair genes are associated with epithelial ovarian cancer. The aim of this study was to evaluate the role of rare, coding, loss-of-function variants across the genome in epithelial ovarian cancer. We carried out a gene-by-gene burden test with various histotypes using data from 2573 non-mucinous cases and 13,923 controls. Twelve genes were associated at a False Discovery Rate of less than 0.1 of which seven were the known ovarian cancer susceptibility genes BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, MSH6 and PALB2. The other five genes were OR2T35, HELB, MYO1A and GABRP which were associated with non-high-grade serous ovarian cancer and MIGA1 which was associated with high-grade serous ovarian cancer. Further support for the association of HELB association comes from the observation that loss-of-function variants in HELB are associated with age at natural menopause and Mendelian randomisation analysis shows an association between genetically predicted age at natural menopause and endometrioid ovarian cancer, but not high-grade serous ovarian cancer.

Adult Cancer Program Lowy Cancer Research Centre University of NSW Sydney NSW Australia

Center for Inherited Oncogenesis Department of Medicine UT Health San Antonio San Antonio Texas USA

Centre for Cancer Research The Westmead Institute for Medical Research Sydney NSW Australia

Department of Biomedical Sciences Cedars Sinai Medical Centre Los Angeles CA USA

Department of Computational Biomedicine Cedars Sinai Medical Centre Los Angeles CA USA

Department of Gynaecological Oncology Westmead Hospital Sydney NSW Australia

Department of Oncology University of Cambridge Cambridge UK

Department of Public Health and Primary Care University of Cambridge Cambridge UK

Department of Research Cancer Registry of Norway Norwegian Institute of Public Health Oslo Norway

Division of Cancer Epidemiology German Cancer Research Center Heidelberg Germany

Division of Cancer Prevention and Control Roswell Park Comprehensive Cancer Center Buffalo NY USA

Division of Gynaecological Oncology Leuven Cancer Institute University Hospital Leuven and KU Leuven Leuven Belgium

Division of Obstetrics and Gynaecology Medical School University of Western Australia Crawley WA Australia

Gynaecology Research Unit Hannover Medical School Hannover Germany

Human Molecular Genetics Laboratory National Centre for Scientific Research Athens Greece

Institute of Medical Biochemistry and Laboratory Diagnostics 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czechia

Keck School of Medicine Division of Medical Oncology University of Southern California Los Angeles CA USA

Mayo Clinic Rochester MN USA

MD Anderson Cancer Center Houston TX USA

Peter MacCallum Cancer Centre Melbourne VIC Australia

QIMR Berghofer Medical Research Institute Brisbane QLD Australia

School of Clinical Medicine Faculty of Medicine and Health University of NSW Sydney NSW Australia

Sir Peter MacCallum Department of Oncology The University of Melbourne Parkville VIC Australia

The Daffodil Centre The University of Sydney A JOINT Venture with Cancer Council NSW Sydney NSW Australia

University of California Los Angeles Los Angeles CA USA

University of Chicago Medicine Comprehensive Cancer Center Chicago IL USA

medRxiv. 2024 Apr 03:2024.04.02.24304968. doi: 10.1101/2024.04.02.24304968. PubMed

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