Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, 3000, Australia.
Sir Peter MacCallum Department of Oncology, The University of Melbourne, Parkville, VIC, 3010, Australia.
Nat Commun. 2020 Apr 2;11(1):1640. 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.
高级别浆液性卵巢癌 (HGSOC) 具有显著的遗传成分，其中约一半无法用已知基因解释。为了发现基因，我们分析了 516 名 BRCA1/2 阴性的 HGSOC 女性的种系外显子组测序数据，重点关注富含罕见、蛋白编码功能丧失 (LoF) 变异的基因。总体而言，病例中存在罕见蛋白编码 LoF 变异的显著富集（p<0.0001，卡方检验）。只有 34 名（6.6%）在已知或拟议的易感性基因中存在致病性变异。少数基因在超过四个个体中具有 LoF 突变，大多数仅在一个个体中检测到。有 43 个高排名基因，这些基因具有三个或更多的 LoF 变异，与 GnomAD 相比，这些变异的富集程度增加了三倍或更多。这些基因代表了多种功能途径，涉及 DNA 修复的基因相对较少，这表明其余的遗传率在很大程度上可以用以前研究较少的基因和途径来解释。
