Prevalence of pathogenic germline variants detected by multigene sequencing in unselected Japanese patients with ovarian cancer

Abstract

Pathogenic germline BRCA1, BRCA2 (BRCA1/2), and several other gene variants predispose women to primary ovarian, fallopian tube, and peritoneal carcinoma (OC), although variant frequency and relevance information is scarce in Japanese women with OC. Using targeted panel sequencing, we screened 230 unselected Japanese women with OC from our hospital-based cohort for pathogenic germline variants in 75 or 79 OC-associated genes. Pathogenic variants of 11 genes were identified in 41 (17.8%) women: 19 (8.3%; BRCA1), 8 (3.5%; BRCA2), 6 (2.6%; mismatch repair genes), 3 (1.3%; RAD51D), 2 (0.9%; ATM), 1 (0.4%; MRE11A), 1 (FANCC), and 1 (GABRA6). Carriers of BRCA1/2 or any other tested gene pathogenic variants were more likely to be diagnosed younger, have first or second-degree relatives with OC, and have OC classified as high-grade serous carcinoma (HGSC). After adjustment for these variables, all 3 features were independent predictive factors for pathogenic variants in any tested genes whereas only the latter two remained for variants in BRCA1/2. Our data indicate similar variant prevalence in Japanese patients with OC and other ethnic groups and suggest that HGSC and OC family history may facilitate genetic predisposition prediction in Japanese patients with OC and referring high-risk patients for genetic counseling and testing.

The first Japanese nationwide multicenter study of BRCA mutation testing in ovarian cancer: CHARacterizing the cross-sectionaL approach to Ovarian cancer geneTic TEsting of BRCA (CHARLOTTE)

“…Alsop et al (Australia) reported a g BRCA mutation prevalence of 17.1% in patients with high-grade serous carcinoma, and Norquist et al (USA) found a combined g BRCA1 and g BRCA2 prevalence of 16.0% 8 19. Nonetheless, the results of our study are consistent with a recent study in Japan that reported a g BRCA prevalence of 29.7% in patients with high-grade serous carcinoma 4. In this study, patients with mucinous cancers did not have g BRCA mutations, which is consistent with the statement of the NCCN guidelines 12.…”

“…Hirasawa et al conducted a single-center study and reported a g BRCA mutation prevalence of 11.7% 4. International studies also reported similar findings; 13.8% in a European and US multicenter study and 12.1% in a Taiwanese study 16 17.…”

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

“…Efforts to identify additional moderate-to-high-risk hereditary breast and ovarian cancer (HBOC) genes have largely been restricted to candidate gene approaches using targeted nextgeneration sequencing (NGS) panels of known cancer predisposition genes [12][13][14][15][16][17][18] , which have collectively only resolved a very small proportion of unexplained families. Although three studies utilised data from whole-exome sequencing (WES) of BRCA1 and BRCA2-negative ovarian carcinoma patients [19][20][21] , these analysed only a subset of candidate genes in the available data and included non-HGSOC tumour types in their case cohorts.…”

Japan Society of Clinical Oncology provisional clinical opinion for the diagnosis and use of immunotherapy in patients with deficient DNA mismatch repair tumors, cooperated by Japanese Society of Medical Oncology, First Edition

“…Whereas for ovarian cancer, the lifetime risk in ordinary groups is 1.5%; for Lynch syndrome, it is 3-20% [30,34,35]. In a recent report in Japan, it was stated that a pathogenic variant of an MMR gene was recognized in 2.6% of epithelial ovarian cancer cases [36].…”