Abstract P1-16-01: High-Resolution Genomic Profiling of Male Breast Cancer Reveals Differences behind the Similarities with Female Breast Cancer

Department of Oncology, Clinical Sciences, Lund University, BMC C13, 22184 Lund, Sweden.
Breast Cancer Research and Treatment (Impact Factor: 3.94). 10/2011; 129(3):747-60. DOI: 10.1007/s10549-010-1262-8
Source: PubMed


Male breast cancer (MBC) is extremely rare and poorly characterized on the molecular level. Using high-resolution genomic data, we aimed to characterize MBC by genomic imbalances and to compare it with female breast cancer (FBC), and further to investigate whether the genomic profiles hold any prognostic information. Fifty-six fresh frozen MBC tumors were analyzed using high-resolution tiling BAC arrays. Significant regions in common between cases were assessed using Genomic Identification of Significant Targets in Cancer (GISTIC) analysis. A publicly available genomic data set of 359 FBC tumors was used for reference purposes. The data revealed a broad pattern of aberrations, confirming that MBC is a heterogeneous tumor type. Genomic gains were more common in MBC than in FBC and often involved whole chromosome arms, while losses of genomic material were less frequent. The most common aberrations were similar between the genders, but high-level amplifications were more common in FBC. We identified two genomic subgroups among MBCs; male-complex and male-simple. The male-complex subgroup displayed striking similarities with the previously reported luminal-complex FBC subgroup, while the male-simple subgroup seems to represent a new subgroup of breast cancer occurring only in men. There are many similarities between FBC and MBC with respect to genomic imbalances, but there are also distinct differences as revealed by high-resolution genomic profiling. MBC can be divided into two comprehensive genomic subgroups, which may be of prognostic value. The male-simple subgroup appears notably different from any genomic subgroup so far defined in FBC.

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    • "There is some overlap in the regions noted previously, with gains at the GNAS locus (20q13.3) and losses at the ATM locus (11q22–23) also seen in MBC and FBC (Rudlowski et al, 2006; Johansson et al, 2011). "
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    ABSTRACT: Male breast cancer (MBC) is still poorly understood with a large proportion arising in families with a history of breast cancer. Genomic studies have focused on germline determinants of MBC risk, with minimal knowledge of somatic changes in these cancers. Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes. Twelve missense mutations included nine PIK3CA mutations (seven in BRCAX patients), two TP53 mutations (both in BRCA2 patients) and one PTEN mutation. Common gains were seen in GNAS (34.1%) and losses were seen in GNAQ (36.4%), ABL1 (47.7%) and ATM (34.1%). Gains of HRAS (37.5% vs 3%, P=0.006), STK11 (25.0% vs 0%, P=0.01) and SMARCB1 (18.8% vs 0%, P=0.04) and the loss of RB1 (43.8% vs 13%, P=0.03) were specific to BRCA2 tumours. This study is the first to perform high-throughput somatic sequencing on familial MBCs. Overall, PIK3CA mutations are most commonly seen, with fewer TP53 and PTEN mutations, similar to the profile seen in luminal A female breast cancers. Differences in mutation profiles and patterns of gene gains/losses are seen between BRCA2 (associated with TP53/PTEN mutations, loss of RB1 and gain of HRAS, STK11 and SMARCB1) and BRCAX (associated with PIK3CA mutations) tumours, suggesting that BRCA2 and BRCAX MBCs may be distinct and arise from different tumour pathways. This has implications on potential therapies, depending on the BRCA status of MBC patients.
    British Journal of Cancer 12/2014; 111(12):2351-60. DOI:10.1038/bjc.2014.511 · 4.84 Impact Factor
    • "All cases of MBC diagnosed between 1983 and 2008 at three Swedish hospitals (Sk ane University Hospital, Uppsala University Hospital, and € Orebro Hospital), with sufficient tumor material available were collected. DNA was extracted as previously described and applied to an array comparative genomic hybridization study (Johansson et al., 2011). The 47 tumors with sufficient remaining DNA were used in the present study. "

    Cancer Research 03/2014; 73(24 Supplement):P1-17-01-P1-17-01. DOI:10.1158/0008-5472.SABCS13-P1-17-01 · 9.33 Impact Factor
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    • "Thus, recommendations for managing MBC have been based on available knowledge and guidelines for FBC. Several studies have nevertheless reported various differences between MBC and FBC based on gene expression (GEX) [2,4], copy number (using array comparative genomic hybridization, aCGH) [1,3], microRNA [9,10] and SNP levels [11]. Among these, we have shown in two previous studies that MBC, like FBC, is a heterogeneous disease, and many differences between MBC and FBC were revealed [1,2]. "
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    ABSTRACT: The rapidly growing collection of diverse genome-scale data from multiple tumor types sheds light on various aspects of the underlying tumor biology. With the objective to identify genes of importance for breast tumorigenesis in men and to enable comparisons with genes important for breast cancer development in women, we applied the computational framework COpy Number and EXpression In Cancer (CONEXIC) to detect candidate driver genes among all altered passenger genes. Unique to this approach is that each driver gene is associated with several gene modules that are believed to be altered by the driver. Thirty candidate drivers were found in the male breast cancers and 67 in the female breast cancers. We identified many known drivers of breast cancer and other types of cancer, in the female dataset (e.g. GATA3, CCNE1, GRB7, CDK4). In contrast, only three known cancer genes were found among male breast cancers; MAP2K4, LHP, and ZNF217. Many of the candidate drivers identified are known to be involved in processes associated with tumorigenesis, including proliferation, invasion and differentiation. One of the modules identified in male breast cancer was regulated by THY1, a gene involved in invasion and related to epithelial-mesenchymal transition. Furthermore, men with THY1 positive breast cancers had significantly inferior survival. THY1 may thus be a promising novel prognostic marker for male breast cancer. Another module identified among male breast cancers, regulated by SPAG5, was closely associated with proliferation. Our data indicate that male and female breast cancers display highly different landscapes of candidate driver genes, as only a few genes were found in common between the two. Consequently, the pathobiology of male breast cancer may differ from that of female breast cancer and can be associated with differences in prognosis; men diagnosed with breast cancer may consequently require different management and treatment strategies than women.
    PLoS ONE 08/2013; 8(10):e78299. DOI:10.1371/journal.pone.0078299 · 3.23 Impact Factor
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