Male breast cancer (MBC) is a rare disease, accounting for <1% of all breast cancer cases. Although it shares many similarities with female breast cancer (FBC), distinct differences in age distribution, levels of hormone receptors, prognosis, as well as on the transcriptional and genomic levels, have been reported. Due to the rarity of the disease, no large comprehensive studies of the etiology of the disease or randomized trials for optimizing patient management have been conducted. Thus, recommendations for managing MBC are extrapolated from prior knowledge and guidelines for FBC.
The aim of this study was to identify candidate driver genes and distinguish them from passenger genes in MBC, an approach that has not been comprehensively explored before. We further compared the landscape of candidate drivers between MBC and FBC, to determine similarities/differences.
To this end, we used the computational framework CONEXIC that integrates array-based comparative genomic hybridization (aCGH) data and gene expression (GEX) data for detecting candidate driver genes. Two datasets with matched aCGH and GEX data were used; one containing 53 MBC tumors and the other containing 359 FBC tumors.
Male and female breast cancers displayed different landscapes of candidate drivers. We correctly identified many of the known drivers for breast cancer and other types of cancer in the FBC dataset (e.g. GATA3, CCNE1, CDK4, GRB7); however these were not replicated among the MBC tumors. Additionally, we identified novel candidate drivers for breast cancer within both the MBC and FBC datasets. When candidate drivers were investigated separately in the intrinsic subgroups of FBC, differences in the landscapes of drivers were observed, with only a few genes overlapping across the subgroups. Interestingly, Rho GTPase activating protein 30, ARHGAP30, was ranked as a top candidate driver for the HER2 and basal FBC subgroups, as well as for MBC. In fact, this was the only candidate driver gene shared between female and male breast cancers. ARHGAP30 binds to the GTPases RhoU/Wrch-1 and overexpression of RhoU is required for migration. The finding that MBC shares a candidate driver gene with the estrogen receptor (ER) negative HER2 and basal FBC subgroups is surprising, given that the majority of the MBC tumors are ER positive.
In summary, the combination of aCGH and GEX data revealed novel candidate driver genes among MBCs, as well as vast differences in the landscapes of candidate drivers between male and female breast cancers. Consequently, the pathobiology of MBC may be very distinct from that of FBC, and men diagnosed with breast cancer may hence require different management and treatment strategies than women.
Citation Format: Ida Johansson, Markus Ringnér, Ingrid Hedenfalk. The landscape of candidate driver genes differs between male and female breast cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 801. doi:10.1158/1538-7445.AM2013-801