Deb S, et al. - Experts planned an investigation to detect methylation of a panel of commonly methylated breast cancer genes in familial male breast cancers (MBCs). A subset of familial MBC was defined by increased methylation, and with average methylation index (AMI) could be a useful prognostic marker.

Methods

• They appraised 60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARβ, CDH1, RUNX3, FOXC1and GSTP1).
• They estimated an average methylation index (AMI) for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation.
• In addition, promoter hypermethylation and AMI were correlated with BRCA carrier mutation status and clinicopathological parameters including tumour stage, grade, histological subtype and disease specific survival.

Results

• In comparison to those arising in non-BRCA2 familial MBCs, tumours arising in BRCA2 mutation carriers showed significantly higher methylation of candidate genes (average AMI 23.6 vs 16.6, p = 0.01, 45% of genes hypermethylated vs 34%, p < 0.01).
• This study highlighted an association of RARβmethylation and AMI-high status with tumour size (p = 0.01 and p = 0.02 respectively), RUNX3methylation with invasive carcinoma of no special type (94% vs 69%, p = 0.046) and RASSF1Amethylation with coexistence of high grade ductal carcinoma in situ (33% vs 6%, p = 0.02).
• Moreover, cluster analysis showed MBCs arising in BRCA2 mutation carriers were characterised by RASSF1A, WIF1, RARβ and GTSP1 methylation (p = 0.02).
• On the other hand, methylation in BRCAX tumours showed no clear clustering to particular genes.
• For disease specific survival, TWIST1 methylation (p = 0.001) and AMI (p = 0.01) were prognostic.