BRCA2 carriers with male breast cancer show elevated tumour methylation

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.Electronic supplementary materialThe online version of this article (10.1186/s12885-017-3632-7) contains supplementary material, which is available to authorized users.

Analysis of Epigenetic Alterations in Homologous Recombination DNA Repair Genes in Male Breast Cancer

“…Although the acquisition of epigenetic alterations, in general, and aberrant DNA methylation, in particular, is widely acknowledged as an early and relevant event in tumorigenesis [29], these have been seldom reported and with different purposes, in male BC [4,[18][19][20][21]. Kornegoor et al, examined promoter methylation of 25 genes in 108 male BCs using methylation specific multiplex ligation dependent probe amplification and concluded that promoter methylation was common in male BC and that high methylation status correlated with aggressive phenotype and poor outcome [18].…”

“…Johanssen et al performed a genome-wide methylation profiling of 47 male BC, underscoring the heterogeneity of this entity and suggesting that male BC should not be defined using conventional criteria applied to female breast cancer [20]. Using methylation-sensitive high resolution, Deb et al assessed a panel of 10 genes in 60 male BCs, concluding that BRCA2-associated male BC was characterized by high gene methylation and that the average methylation index might be a useful prognostic marker [4]. Finally, Rizzolo et al assessed promoter methylation in 69 male BC patients and concluded that alterations in methylation patterns were common in BC and might identify specific subgroups related to BRCA1/2 mutation status and some clinicopathologic parameters [21].…”

“…The process of carcinogenesis is complex, resulting from the accumulation of multiple genetic and epigenetic alterations [4]. The best characterized epigenetic change in cancer consists on altered methylation of CpG dinucleotides, impacting on genome stability and regulation of gene expression [5].…”

“…Nonetheless, HRR deficiency may also be mediated by DNA repair gene aberrant promoter methylation. Although altered DNA methylation has been seldom reported in male BC, it might constitute a novel biomarker for disease detection and monitoring, allowing for more personalized clinical care [4,[18][19][20][21].…”

Young male breast cancer, a small crowd, the survival, and prognosis?

“…Several studies have pointed that a significant number of patients (mostly BRCA2 mutation positive) developed multiple cancers including male breast cancer; most male cancers are ER positive but without a corresponding increase in PR positivity and only a weaker association with estrogen-controlled markers such as PS2, HSP27, and Cathepsin D; increased methylation defines a subset of familial male breast cancer and with average methylation index may be a useful prognostic marker. [ 32 – 34 ]…”