MosaicBRCA1promoter methylation contribution in hereditary breast/ovarian cancer pedigrees

Abstract

PurposeMosaicBRCA1promoter methylation (BRCA1meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaicBRCA1meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed.PatientsBlood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants inBRCA1/2,PALB2orRAD51C/D, were screened by methylation-sensitive high-resolution melting. CpG analysis was performed by pyrosequencing on blood and buccal swab. Two probands carried a pathogenic variant in a moderate-penetrance gene (ATMandBARD1), and 8 of 18 others (44%) carriedBRCA1meth (vs none of the 20 age-matched controls). Involvement ofBRCA1in tumourigenesis in methylated probands was demonstrated in most tested cases by detection of a loss of heterozygosity and a homologous recombination deficiency signature. Among the eight methylated probands, two had relatives with breast cancer with detectableBRCA1meth in blood, including one with high methylation levels in two non-tumour tissues.ConclusionsThe high prevalence of mosaicBRCA1meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaicBRCA1meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees.