Abstract LB-159: Methylation of BRCA1 gene in blood is not inherited via maternal germ line and may predispose to triple-negative or medullary breast cancer

Abstract

Abstract Methylation of the BRCA1 gene in peripheral blood (epimutation) has been associated with pathology of early onset breast cancer (1). This epimuataion was suggested to be of constitutional origin and hence can potentially be transmitted to the next generation as previously reported for MLH1 gene (2). We used methylation sensitive high resolution melting technique (MS-HRM) (3) to measure methylation of BRCA1 gene in blood samples from 226 healthy women from the Andean region in northern Argentina. In total 29 (13%) of the women showed detectable methylation of this gene. The analyses of mother-daughter pairs (n = 6) in this study, showed discordant methylation of BRCA1 between generations, with mothers that tested positive having daughters that tested negative for BRCA1 methylation, and vice versa. This indicates that the BRCA1 epimutation is not transmitted from mother to daughters via the maternal germline. Furthermore we conducted a case-control study of 66 breast cancer cases and 36 unaffected controls of polish women selected from registry of International Hereditary Cancer Centre (IHCC), Department of Genetics and Pathology, Pomeranian Medical University, Szczecin, Poland. Cases were triple-negative or of medullary histology, or both; 30 carried a constitutional BRCA1 mutation and 36 did not carry a mutation. Methylation of the BRCA1 promoter was detected in 15 of 66 cases and in 2 of 36 controls (OR 5.0, p = 0.03). Methylation was present in 15 of 36 women with breast cancer and without germline BRCA1 mutation, but in none of 30 women with breast cancer and a germline mutation (p < 0.01). The association between methylation and breast cancer was restricted to women with no constitutional BRCA1 mutation (OR 12.1, p = 0.0006) (4). In conclusion it is unlikely that epimutation of BRCA1 is inherited through maternal germ line and this epimutation may be a marker of increased susceptibility to triple-negative or medullary breast cancer.