Journal article
Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing
DN Subramanian, M Zethoven, KI Pishas, ER Marinović, S McInerny, SM Rowley, PE Allan, L Devereux, D Cheasley, PA James, IG Campbell
Npj Genomic Medicine | NATURE PORTFOLIO | Published : 2025
Abstract
High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, only half of which is explained. Previously, we performed germline exome sequencing on BRCA1 and BRCA2-negative HGSOC patients, revealing three proposed and 43 novel candidate genes enriched with rare loss-of-function variants. For validation, we undertook case-control analyses using genomic data from disease-free controls. This confirms enrichment for nearly all previously identified genes. Additionally, one-hundred-and-eleven HGSOC tumours from variant carriers were sequenced alongside other complementary studies, seeking evidence of biallelic inactivation as supportive evidence. PALB2 and ATM validate as H..
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Grants
Awarded by National Breast Cancer Foundation
Funding Acknowledgements
The authors thank the staff at the Victorian and Tasmanian Familial Cancer Centres who enrolled participants and provided clinical data, A/Prof. Heather Thorne and the staff at kConFab for assisting with retrieval of archival tumour material, along with all ViP study participants for donating their DNA samples and consenting to share their clinical information and tumour material. DNS additionally thanks Prof. David Thomas, for facilitating access to the MGRB data; Dr. Suad Abdirahman, for technical advice regarding the IHC; Theresa Wang, for assisting with tumour sample cataloguing, microdissection, and DNA extraction; Qihong Zhao, for organising paired germline-tumour WGS; and both A/Prof. Kylie Gorringe and Prof. Ingrid Winship AO, for their general advice and support. This work was supported by a National Health and Medical Research Council Program Grant (APP1092856 to IGC and PAJ), and Medical/Dental Postgraduate Scholarship (GNT1134107 to DNS), as well as a Cancer Council Victoria grant (CCV 21/24 to IGC), National Breast Cancer Foundation grant (IIRS-22-027 to IGC), Medical Research Futures Fund grant (APP-2008678 to IGC) and Australian Government Research Training Program Scholarship (to DNS). The funding sources did not participate in the design and conduct of the study, the collection, analysis, and interpretation of the data, the preparation and writing of the manuscript, and the decision to submit the manuscript for publication.