Pathogenic variants in BRCA1 or BRCA2 are identified in ~20% of families with multiple individuals with early-onset breast/ovarian cancer. Extensive searches for additional highly penetrant genes or alternative mutational mechanisms altering BRCA1/2 have not explained the missing heritability.Here, we report a dominantly inherited 5’UTR variant associated with epigenetic silencing of BRCA1 due to promoter hypermethylation in two families with breast/ovarian cancer.
BRCA1 promoter methylation of ten CpG dinucleotides in breast/ovarian cancer families without germline BRCA1/2 pathogenic variants was assessed by pyrosequencing and clonal bisulfite sequencing. RNA and DNA sequencing of BRCA1 from lymphocytes was undertaken to establish allelic expression and the presence of germline variants.
BRCA1 promoter hypermethylation was identified in two of 49 families with multiple women affected with grade 3 breast/high grade serous ovarian cancer. Soma-wide BRCA1 promoter hypermethylation was confirmed in blood, buccal mucosa and hair follicles. Methylation levels were ~50%, consistent with the silencing of one allele and confirmed by clonal bisulfite sequencing. RNA sequencing revealed allelic loss of BRCA1 expression in both families and this segregated with a heterozygous variant c.-107A>T in the BRCA1 5’UTR.
Our results indicate a novel mechanism for familial breast/ovarian cancer, caused by an in cis 5’UTR variant associated with epigenetic silencing of the BRCA1 promoter in two independent families. We propose that methylation analyses are undertaken to establish the frequency of this mechanism in families affected by early onset breast/ovarian cancer without a BRCA1/2 pathogenic variant.