Journal article

Exome sequencing of familial high-grade serous ovarian carcinoma reveals heterogeneity for rare candidate susceptibility genes

Deepak N Subramanian, Magnus Zethoven, Simone McInerny, James A Morgan, Simone M Rowley, Jue Er Amanda Lee, Na Li, Kylie L Gorringe, Paul A James, Ian G Campbell

Nature Communications | NATURE PUBLISHING GROUP | Published : 2020


High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2-negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases (p < 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four individuals and the majority are detected in one individual only. Forty-three highly-ranked gene..

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Awarded by National Health and Medical Research Council

Funding Acknowledgements

The authors wish to thank the staff at the Victorian and Tasmanian Familial Cancer Centres who enrolled participants and provided clinical data, and we thank all the participants of the ViP study for donating their DNA samples and consenting to share their clinical information. D.N.S. wishes to thank the staff in the Bioinformatics Core Facility as well as Dr. Elizabeth Christie and Prof. Ingrid Winship for their advice and support. This work was supported by a National Health and Medical Research Council Program Grant (APP1092856 to I.G.C. and P.A.J.) and Medical/Dental Postgraduate Scholarship (GNT1134107 to D.N.S.), and an Australian Government Research Training Program Scholarship.