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.2013 Oct 23;8(10):e78299.
doi: 10.1371/journal.pone.0078299. eCollection 2013.

The landscape of candidate driver genes differs between male and female breast cancer

Affiliations

The landscape of candidate driver genes differs between male and female breast cancer

Ida Johansson et al. PLoS One..

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.

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Conflict of interest statement

Competing Interests:The authors have declared that no competing interests exist.

Figures

Figure 1
Figure 1. Flowchart outlining the steps in the CONEXIC analysis.
Figure 2
Figure 2. Heatmap of the genes in the module regulated byTHY1 in MBC.
Red corresponds to up-regulation and green to down-regulation. The 66 MBC tumors are sorted according to their gene expression level ofTHY1.
Figure 3
Figure 3. Heatmap of the genes in the module regulated bySPAG5 in MBC.
Red corresponds to up-regulation and green to down-regulation. The 66 MBC tumors are sorted according to their gene expression level ofSPAG5.
Figure 4
Figure 4. Graphic output of the LitVAn result for the MBCTHY1 module and corresponding Kaplan-Meier survival analysis.
A) Significantly over-represented terms are represented as red circles and their association (graph edges) with multiple genes (yellow circles) from the module. The green dots represent the publication that significantly associates between the gene and the term, and the numbers in the green dots are the PubMed IDs for the respective publications.B) Distant metastasis free survival of the 66 MBC patients stratified byTHY1 gene expression. The numbers below the plots indicate the number of patients at risk in each group at the given time points.
Figure 5
Figure 5. Graphic output of the LitVAn result for the MBCSPAG5 module and corresponding Kaplan-Meier survival analysis.
A) Significantly over-represented terms are represented as red circles and their association (graph edges) with multiple genes (yellow circles) from the module. The green dots represent the publication that significantly associates between the gene and the term, and the numbers in the green dots are the PubMed IDs for the respective publications.B) Distant metastasis free survival of the 66 MBC patients stratified bySPAG5 gene expression. The numbers below the plots indicate the number of patients at risk in each group at the given time points.
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References

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