Promoter hypermethylation in male breast cancer: analysis by multiplex ligation-dependent probe amplification

Abstract

IntroductionEpigenetic events are, along with genetic alteration, important in the development and progression of cancer. Promoter hypermethylation causes gene silencing and is thought to be an early event in carcinogenesis. The role of promoter hypermethylation in male breast cancer has not yet been studied.MethodsIn a group of 108 male breast cancers, the methylation status of 25 genes was studied using methylation-specific multiplex ligation-dependent probe amplification. Methylation of more than 15% was regarded indicative for promoter hypermethylation. Methylation status was correlated with clinicopathological features, with patients' outcome and with 28 female breast cancer cases.ResultsPromoter hypermethylation of the genes MSH6, WT1, PAX5, CDH13, GATA5 and PAX6 was seen in more than 50% of the cases, but was uncommon or absent in normal male breast tissue. High overall methylation status was correlated with high grade (P = 0.003) and was an independent predictor of poor survival (P = 0.048; hazard ratio 2.5). ESR1 and GSTP1 hypermethylation were associated with high mitotic count (P = 0.037 and P = 0.002, respectively) and high grade (both P = 0.001). No correlation with survival was seen for individual genes. Compared with female breast cancers (logistic regression), promoter hypermethylation was less common in a variety of genes, particularly ESR1 (P = 0.005), BRCA1 (P = 0.010) and BRCA2 (P < 0.001). The most frequently hypermethylated genes (MSH6, CDH13, PAX5, PAX6 and WT1) were similar for male and female breast cancer.ConclusionPromoter hypermethylation is common in male breast cancer and high methylation status correlates with aggressive phenotype and poor survival. ESR1 and GSTP1 promoter hypermethylation seem to be involved in development and/or progression of high-grade male breast cancer. Although female and male breast cancer share a set of commonly methylated genes, many of the studied genes are less frequently methylated in male breast cancer, pointing towards possible differences between male and female breast carcinogenesis.

A Case-Matched Gender Comparison Transcriptomic Screen Identifies eIF4E and eIF5 as Potential Prognostic Markers in Male Breast Cancer

“…The need for more refined therapeutic treatments for male breast cancer (MBC) is evidenced by a steady stream of publications highlighting gender-specific differences using IHC (1-5), genetics (6)(7)(8)(9)(10)(11), and more recently, epigenetics (12)(13)(14)(15). Of note, although MBC is similar histologically to female breast cancer (FBC), with the same panel of biomarkers used to guide treatment and prognosis, more rigorous interrogation of the underlying genetics shows heterogeneity in MBC as recognized in FBC where molecular profiling has identified different subgroups that correlate with varying clinical outcomes.…”

Clonal intratumor heterogeneity of promoter hypermethylation in breast cancer by MS-MLPA

“…Nevertheless, it was recently shown that DNA methylation was maintained across all prostatic metastases within the same individual, indicating that these epigenetic alterations can be stably maintained as driver genome alterations fueling cancer initiation and progression. 13 Aberrant DNA methylation has been observed in all types and stages of cancer, including breast cancer, [18][19][20] and measurement of the methylation status of specific genes in tumor tissue or blood can aid early detection of cancer, determine prognosis and predict therapy responses. 21 A wide range of techniques is available to determine tumor methylation levels, 22 some of them with very high resolution (such as quantitative multiplex methylation-specific PCR) but often requiring bisulfite conversion and a focused approach, and others with lower resolution (such as MSP and methylation-specific multiplex ligationdependent probe amplification or MS-MLPA).…”

Genome methylation patterns in male breast cancer – Identification of an epitype with hypermethylation of polycomb target genes

“…Interestingly, hypermethylation of CpGs in promoter islands was significantly more common in ME1 tumors, potentially also suggesting different mechanisms of gene regulation among some MBCs. In line with these data, a recent study showed that high promoter methylation frequencies of 25 tumor suppressor genes were associated with an aggressive phenotype and poor survival in a cohort of approximately 100 MBCs (Kornegoor et al., 2012).…”