Assessment of candidate high-grade serous ovarian carcinoma predisposition genes through integrated germline and tumour sequencing
- Author(s)
- Subramanian, DN; Zethoven, M; Pishas, KI; Marinović, ER; McInerny, S; Rowley, SM; Allan, PE; Devereux, L; Cheasley, D; James, PA; Campbell, IG;
- Details
- Publication Year 2025-01-10,Volume 10,Issue #1,Page 1
- Journal Title
- NPJ Genomic Medicine
- Publication Type
- Research article
- 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 HGSOC predisposition genes, with 6/8 germline carrier tumours exhibiting biallelic inactivation accompanied by characteristic mutational signatures. Among candidate genes, only LLGL2 consistently shows biallelic inactivation and protein expression loss, supporting it as a novel HGSOC susceptibility gene. The remaining candidate genes fail to validate. Integrating case-control analyses with tumour sequencing is thus crucial for accurate gene discovery in familial cancer studies.
- Publisher
- Springer Nature
- Department(s)
- Laboratory Research; Familial Cancer Centre; Pathology
- Publisher's Version
- https://doi.org/10.1038/s41525-024-00447-3
- Open Access at Publisher's Site
https://doi.org/10.1038/s41525-024-00447-3- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2025-01-23 02:18:55
Last Modified: 2025-01-23 02:30:24