Abstract P1-17-01: Whole genome methylation patterns in male and female breast cancer – Unexpected findings

Abstract

Abstract Male breast cancer (MBC) is a rare disease, accounting for less than 1% of all breast cancer cases. Although it is similar to female breast cancer (FBC) in many ways, distinct differences in incidence, age distribution, levels of hormone receptors, prognosis and survival have been reported. In a recent gene expression profiling study of MBC we described two new subgroups (Luminal M1 and M2, respectively) that did not resemble any of the intrinsic subgroups reported in FBC, and as such may be specific to breast cancer in men. Luminal M1 tumors (70% of the MBC tumors) seemed to be more aggressive and were associated with worse prognosis and also appeared to have a less activated estrogen receptor (ER) pathway, while Luminal M2 tumors (30% of the MBC tumors) displayed an up-regulated immune response and a more activated ER pathway. This despite >90% of the MBCs being ER positive by immunohistochemistry. Due to the rarity of the disease, no large comprehensive trials for optimizing patient management have been conducted to date. Recommendations for management of MBC are therefore extrapolated from knowledge of FBC. The aim of this study was to assess genome wide methylation profiles in primary human MBC and compare them with the transcriptionally derived subgroups, Luminal M1 and M2, as well as FBC. Epigenetic changes are known to be involved in tumorigenesis and methylation may influence the expression of cancer related genes and are potential druggable targets. We used Illumina's 450K arrays to measure global methylation profiles in 47 MBC and 215 FBC tumors, representing all subgroups of male and female breast cancers. Unsupervised hierarchical clustering of the most variable probes among the MBC tumors revealed two stable subgroups. The methylation patterns differed significantly between the groups and were associated with the transcriptional subgroups Luminal M1 and M2. When the MBC and FBC tumors were analyzed together using the most variable probes, three stable clusters were identified. The Basal-like FBC tumors formed one cluster and the other two clusters were associated with Luminal A and B FBC tumors, respectively, while the HER2 FBCs were split between the Luminal A and B clusters. The majority of the Luminal M1 tumors clustered with the Luminal Bs while the Luminal M2 tumors clustered with the Luminal As. However, the majority of the MBC tumors were grouped together within the clusters rather than being interspersed with the FBC tumors, suggesting that they differed from the FBC tumors in the respective clusters. Interestingly, the Luminal M2 MBCs and Basal-like FBCs displayed a significantly higher frequency of hypomethylation compared to all other subgroups, despite Luminal M1 tumors being more similar to Basal-like tumors on a transcriptional level than the Luminal M2 tumors. To summarize, we have described two subgroups of MBC based on genome wide methylation patterns, closely resembling the transcriptional subgroups, and associated with different tumor biological features of potential clinical relevance. These findings further suggest that MBC is not readily defined using conventional criteria applied to FBC. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P1-17-01.