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.

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

“…Furthermore, evidence of significant hereditary predisposition was found in this cohort (FH of breast cancer, BRCA2 mutations and NBPN, in 20.3%, 32.4%, and 15.5% of cases, respectively) which is line with published literature [26,27]. Furthermore, the clinical and pathological characteristic of the patient population are also similar to those previously published [3,21,28], which further validates our dataset.…”

“…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].…”

“…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].…”

“…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].…”

Genome‑wide methylation profiles in monozygotic twins with discordance for ovarian carcinoma

“…Previous studies reported that AR promoter hypermethylation was associated with decreased AR expression in breast cancer cell lines ( 38 ), and that AR gene promoter methylation was higher in patients with wild-type BRCA1 /2 compared with mutated BRCA1 /2 in men diagnosed with breast cancer ( 39 ). In general, the data in the literature indicate that AR is associated with male breast cancer ( 39 ). The detection of hypermethylated AR in the brother with wild-type BRCA1 in the present study is consistent with the literature.…”