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

• Published in: Nature communications Vol. 11; no. 1; p. 1640
• Main Authors: Subramanian, Deepak N., Zethoven, Magnus, McInerny, Simone, Morgan, James A., Rowley, Simone M., Lee, Jue Er Amanda, Li, Na, Gorringe, Kylie L., James, Paul A., Campbell, Ian G.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-04-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 45/23; 692/308/2056; 692/420/2489/68; 692/699/67/1517/1709; Adult; Aged; Aged, 80 and over; BRCA1 protein; Chi-square test; Cohort Studies; Cystadenocarcinoma, Serous - genetics; Cystadenocarcinoma, Serous - pathology; Deoxyribonucleic acid; DNA; DNA repair; Enrichment; Exome; Exome Sequencing; Female; Genes; Genetic Heterogeneity; Genetic Predisposition to Disease; Heritability; Heterogeneity; Humanities and Social Sciences; Humans; Loss of Function Mutation; Middle Aged; multidisciplinary; Mutation; Ovarian cancer; Ovarian carcinoma; Ovarian Neoplasms - genetics; Ovarian Neoplasms - pathology; Proteins; Science; Science (multidisciplinary); Statistical tests; Young Adult
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-15461-z

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 genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent diverse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.
Around half of the heritability underpinning familial high-grade serous ovarian carcinoma remains unidentified. Here, the authors show that extremely rare protein encoding loss-of-function variants, with a high degree of genetic heterogeneity, may account for some of this missing heritability.