Abstract
BackgroundMale breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. However, recent studies demonstrate biological and molecular differences likely to impact on tumour behaviour and therefore patient outcome. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs.Methods60 tumours from 3 BRCA1 and 25 BRCA2 male mutation carriers and 32 males from BRCAX families were assessed for promoter methylation by methylation-sensitive high resolution melting in a panel of 10 genes (RASSF1A, TWIST1, APC, WIF1, MAL, RARβ, CDH1, RUNX3, FOXC1 and GSTP1). An average methylation index (AMI) was calculated for each case comprising the average of the methylation of the 10 genes tested as an indicator of overall tumour promoter region methylation. Promoter hypermethylation and AMI were correlated with BRCA carrier mutation status and clinicopathological parameters including tumour stage, grade, histological subtype and disease specific survival.ResultsTumours arising in BRCA2 mutation carriers showed significantly higher methylation of candidate genes, than those arising in non-BRCA2 familial MBCs (average AMI 23.6 vs 16.6, p = 0.01, 45% of genes hypermethylated vs 34%, p < 0.01). RARβ methylation and AMI-high status were significantly associated with tumour size (p = 0.01 and p = 0.02 respectively), RUNX3 methylation with invasive carcinoma of no special type (94% vs 69%, p = 0.046) and RASSF1A methylation with coexistence of high grade ductal carcinoma in situ (33% vs 6%, p = 0.02). Cluster analysis showed MBCs arising in BRCA2 mutation carriers were characterised by RASSF1A, WIF1, RARβ and GTSP1 methylation (p = 0.02) whereas methylation in BRCAX tumours showed no clear clustering to particular genes. TWIST1 methylation (p = 0.001) and AMI (p = 0.01) were prognostic for disease specific survival.ConclusionsIncreased methylation defines a subset of familial MBC and with AMI may be a useful prognostic marker. Methylation might be predictive of response to novel therapeutics that are currently under investigation in other cancer types.
Highlights
Male breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer
It is well recognised that aberrant modification of gene expression by promoter methylation is often pathogenic and not an inconsequential contributor to oncogenesis: epigenomic changes are often more commonly observed than gene mutations and chromosomal instability in many cancers [6]
Sixty cases had sufficient material at an appropriate DNA concentration for methylation testing as outlined below. These cases belonged to three groups: 3 MBCs that arose in BRCA1 mutation carriers, 25 that arose in BRCA2 mutation carriers and 32 that occurred in males from BRCAX families
Summary
Male breast cancer (MBC) represents a poorly characterised group of tumours, the management of which is largely based on practices established for female breast cancer. The aim of this study was to investigate methylation of a panel of commonly methylated breast cancer genes in familial MBCs. Male breast cancer (MBC) is a poorly studied disease. As a significant proportion of MBCs arise within breast/ovarian families, the majority of MBC research has focused on cancer predisposition. Differences in genotype-phenotype between female and male breast cancers suggest that MBCs have alternate and novel drivers [3,4,5]. It is well recognised that aberrant modification of gene expression by promoter methylation is often pathogenic and not an inconsequential contributor to oncogenesis: epigenomic changes are often more commonly observed than gene mutations and chromosomal instability in many cancers [6]. Aberrant methylation is frequently seen within CpG islands in promoter regions often resulting in transcriptional silencing [7] often occurring early in cancer development
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