Chromosome 17 copy number changes in male breast cancer

Abstract

BackgroundOverall, HER2-amplified female breast cancer (FBC) is associated with a high grade, an aggressive phenotype and a poor prognosis. In male breast cancer (MBC) amplification of HER2, located on chromosome 17, occurs at a lower frequency than in FBC, where it is part of complex rearrangements. So far, only few studies have addressed the occurrence of chromosome 17 alterations in small MBC cohorts.MethodsMultiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH) were used to detect and characterize copy number changes on chromosome 17 in a cohort of 139 MBC. The results obtained were compared to those in FBC, and were correlated with clinicopathological features and patient outcome data.ResultsWe observed a lower frequency of chromosome 17 copy number changes with less complex rearrangement patterns in MBC compared to FBC. Chromosome 17 changes in MBC included gains of 17q and losses of 17p. Whole chromosome 17 polyploidies were not encountered. Two recurrent chromosome 17 amplicons were detected: on 17q12 (encompassing the NEUROD2, HER2, GRB7 and IKZF3 gens) and on 17q23.1 (encompassing the MIR21 and RPS6KB1 genes). Whole arm copy number gains of 17q were associated with decreased 5 year survival rates (p = 0.010). Amplification of HER2 was associated with a high tumor grade, but did not predict patient survival. Although copy number gains of HER2 and NEUROD2 were associated with a high tumor grade, a high mitotic count and a decreased 5 year survival rate (p = 0.015), only tumor size and NEUROD2 copy number gains emerged as independent prognostic factors.ConclusionsIn MBC chromosome 17 shows less complex rearrangements and fewer copy number changes compared to FBC. Frequent gains of 17q, encompassing two distinct amplicons, and losses of 17p were observed, but no whole chromosome 17 polyploidies. Only NEUROD2 gains seem to have an independent prognostic impact. These results suggest different roles of chromosome 17 aberrations in male versus female breast carcinogenesis.Electronic supplementary materialThe online version of this article (doi:10.1007/s13402-015-0227-7) contains supplementary material, which is available to authorized users.

p53 and miR‐210 regulated NeuroD2, a neuronal basic helix–loop–helix transcription factor, is downregulated in glioblastoma patients and functions as a tumor suppressor under hypoxic microenvironment

“…Beyond these classical features, there is very little known about NeuroD2 and its relation to tumor biology. A very recent report suggests NeuroD2 to be highly amplified along with neighboring genes GRB7 and IKZF3 in HER2 amplicon in male breast cancer . Copy number gain of NeuroD2 was also found to be correlated with overall poor survival, high mitotic count and high tumor grade in male breast cancer .…”

“…A very recent report suggests NeuroD2 to be highly amplified along with neighboring genes GRB7 and IKZF3 in HER2 amplicon in male breast cancer. 7 Copy number gain of…”

“…NeuroD2 was also found to be correlated with overall poor survival, high mitotic count and high tumor grade in male breast cancer. 7 Another report suggests that NeuroD2 is overexpressed in medulloblastomas. 8 In contrast, NeuroD2 was found to upregulate the expression of cyclin-dependent kinase inhibitor 1B (p27KIP1), a well-known tumor suppressor gene, that regulates the cell cycle progression at G1.…”

“…NeuroD2 is overexpressed in male breast cancer and medulloblastoma, however, its causative role in these cancers has not yet been demonstrated. 7,8 NeuroD2 has been shown to play a role in the determination and maintenance of neuronal cell fates. 3 Transcription Factor (REST), which is transcriptionally inhibited by NeuroD2 during neuronal differentiation, 9 works as an oncogenic controller in GBM stem cells.…”

Non-HER2 signaling pathways activated in resistance to anti-HER2 therapy in breast cancer

“…Copy number changes involving gains in NEUROD2 (p = 0.015), HER2 (p = 0.015) and in the whole arm of chromosome 17q (p = 0.010) have recently shown to decrease the 5-year survival rate in 139 male MBC [91].…”