MosaicBRCA1promoter methylation contribution in hereditary breast/ovarian cancer pedigrees

Purpose Mosaic BRCA1 promoter methylation ( BRCA1 meth) increases the risk of early-onset breast cancer, triple-negative breast cancer and ovarian cancer. As mosaic BRCA1 meth are believed to occur de novo, their role in family breast/ovarian cancer has not been assessed. Patients Blood-derived DNA from 20 unrelated affected cases from families with aggregation of breast/ovarian cancer, but with no germline pathogenic variants in BRCA1 / 2 , PALB2 or RAD51C/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 ( ATM and BARD1 ), and 8 of 18 others (44%) carried BRCA1 meth (vs none of the 20 age-matched controls). Involvement of BRCA1 in 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 detectable BRCA1 meth in blood, including one with high methylation levels in two non-tumour tissues. Conclusions The high prevalence of mosaic BRCA1 meth in patients with breast/ovarian cancer with affected relatives, as well as this first description of a family aggregation of mosaic BRCA1 meth, shows how this de novo event can contribute to hereditary breast/ovarian cancer pedigrees.