Prevalence of germline pathogenic BRCA1/2 variants in sequential epithelial ovarian cancer cases

Abstract

IntroductionPoly(ADP-ribose) polymerase inhibitors significantly improve progression-free survival in platinum-sensitive high-grade serous and endometrioid ovarian carcinoma, with greatest benefits observed in women with a pathogenic BRCA1/2 variant. Consequently, the demand for germline BRCA1/2 testing in ovarian cancer has increased substantially, leading to the screening of unselected populations of patients. We aimed to determine the prevalence of pathogenic germline BRCA1/2 variants in women diagnosed with epithelial ovarian cancer, categorised according to the established risk factors for hereditary breast and ovarian cancer syndrome and the Manchester BRCA Score, to inform risk stratification.MethodsA cohort of sequential epithelial ovarian cancer cases recruited between June 2013 and September 2018 underwent germline BRCA1/2 testing by next-generation sequencing and multiplex ligation-dependent probe amplification.ResultsFive hundred and fifty-seven patients were screened. Of these, 18% had inherited a pathogenic BRCA1/2 variant. The prevalence of pathogenic BRCA1/2 variants was >10% in women diagnosed with ovarian cancer earlier than 60 years of age (21%) and those diagnosed later than 60 years of age with a family history of breast and/or ovarian cancer (17%) or a medical history of breast cancer (34%). The prevalence of pathogenic BRCA1/2 variants was also >10% in women with a Manchester BRCA Score of ≥15 points (14%).DiscussionOur study suggests that age at diagnosis, family history of breast and/or ovarian cancer, medical history of breast cancer or a Manchester BRCA Score of ≥15 points are associated with a >10% prevalence of germline pathogenic BRCA1/2 variants in epithelial ovarian cancer.

Gene Panel Tumor Testing in Ovarian Cancer Patients Significantly Increases the Yield of Clinically Actionable Germline Variants beyond BRCA1/BRCA2

“…Almost all patients included in this study were also tested for BRCA1 and BRCA2 somatic and germline variants using a clinically validated method [ 16 ], and this study was able to identify all 15 patients known to be carriers of deleterious BRCA1/BRCA2 germline variants, which allowed validation of the custom panel we designed for those genes. The frequency of pathogenic BRCA1 and BRCA2 germline variants in this unselected series of OC patients was 13.7%, which is in concordance with previous studies that reported frequencies between 13% and 18% [ 12 , 16 , 19 , 20 , 21 ]. Furthermore, BRCA1 / BRCA2 tumor sequencing allows the detection of both germline and somatic variants in a single test, the latter having a frequency ranging from 4% to 7% [ 16 , 22 , 23 ].…”

Multigene Panel Germline Testing of 1333 Czech Patients with Ovarian Cancer

“…BRCA1 mutations dominated in patients <60 years over BRCA2 mutations, while in patients ≥ 60 years, their frequencies were comparable. Moreover, we revealed 29 BRCA1/2 mutation carriers (13.9% of patients) in 208 OC patients diagnosed at ≥60 years with no family cancer history, while Morgan and colleagues detected only two (4.3%) BRCA1/2 mutations in 46 sporadic OC patients ≥ 60 years [33]. Even in the oldest subgroup of our OC patients diagnosed at ≥70 years, the frequency of BRCA1/2 mutation carriers exceeded 18%, while in other studies, BRCA1/2 mutations' frequency in this age category was below 10% [34,35].…”

30 year experience of index case identification and outcomes of cascade testing in high-risk breast and colorectal cancer predisposition genes

“…This likely reflects the increased penetrance of BRCA1 as compared with BRCA2 despite BRCA2 alterations being more common in the population as exemplified by gnomAD data [gnomAD v2.1.1 accessed 15th February 2021 BRCA1 loss of function (LoF), n = 141; BRCA2 LoF, n = 248], control frequencies from the BRIDGES study [ 23 ] and a recent population study in the USA [ 18 ]. Germline BRCA1 variants are often associated with young-onset life-limiting grade 3 triple-negative breast cancers [ 24 ], whereas for women ≥60 years with no previous cancer history who develop an epithelial ovarian cancer, BRCA2 variants are more frequently detected [ 25 ].…”