Gene-specific methylation profiles in BRCA-mutation positive and BRCA-mutation negative male breast cancers

Abstract

Male breast cancer (MBC) is a rare disease. Due to its rarity, MBC research and clinical approach are mostly based upon data derived from female breast cancer (FBC). Increasing evidence indicate that on molecular level MBC may be an heterogeneous disease different from FBC. In order to investigate whether epigenetic signatures could define molecular subgroups of MBCs, we performed promoter methylation analysis of genes involved in signal transduction and hormone signalling in BRCA1/2 mutation-positive and -negative MBCs. We examined 69 MBCs, paired blood samples, and 15 normal tissues for promoter methylation of hTERT, ESR1, RASSF1, AR, MYC and WNT1 genes. MBCs showed higher gene promoter methylation levels compared to paired blood and normal breast samples. Significantly higher RASSF1 methylation levels were observed in association with BRCA1/2 mutations, HER2 expression and high tumor grade. Significantly higher AR methylation levels were observed in BRCA1/2 wild-type cases and higher WNT1 methylation levels in PR negative cases. Overall, our results indicate that alterations in gene methylation profiles are common in MBC and that methylation pattern of tumor-associated genes may allow for the identification of MBC molecular subgroups, that could have implications in clinical management of MBC patients.

Keywords: BRCA1/2 mutations; clinical-pathologic characteristics; male breast cancer; promoter methylation; pyrosequencing.

Figure 1

(A) Distribution of the methylation levels in different tissue samples from male breast cancer cases. Boxplots show comparison of median methylation levels of hTERT, WNT1, AR, MYC, ESR1 and RASSF1 genes in blood, lymph node, normal breast and tumor breast samples. (B) Unsupervised hierarchical clustering analysis of promoter methylation levels of 6 genes in 64 male breast turmors.