A systematic review on the frequency of BRCA promoter methylation in breast and ovarian carcinomas of BRCA germline mutation carriers: Mutually exclusive, or not?

Background: A considerable number of breast and ovarian carcinomas are due to underlying BRCA gene aberrations. Of these, BRCA germline mutations and BRCA promoter methylation are thought to be mutually exclusive, which could be exploited in clinical practice. However, this paradigm has not been studied extensively and systematically. Objective: To systematically investigate to what extent BRCA promoter methylation has been reported in breast and ovarian carcinomas of BRCA germline mutation carriers. Methods: A comprehensive search on BRCA promoter methylation was performed in PubMed and Embase databases. Two authors independently selected studies, assessed study quality and extracted data according to PRISMA and QUADAS-2 guidelines. Results: 21 articles met the inclusion criteria. BRCA1 methylation was found in at least 10/276 (3,6%) breast and 2/174 (1,1%) ovarian carcinomas of BRCA germline mutation carriers, and BRCA2 methylation was found in at least 7/131 (5.3%) breast and 0/51 (0.0%) ovarian carcinomas of BRCA germline mutation carriers. Methylation frequencies varied between individual CpG sites. The selected studies showed important differences in methodology and performed in general a limited methylation and incomplete mutation analysis. Conclusions: BRCA methylation is rare in breast and ovarian carcinomas of BRCA germline mutation carriers, although the frequency of BRCA promoter methylation may be underestimated. This could have major implications for clinical practice, including referral for genetic testing and BRCAness analysis for treatment decision-making.