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Oncogenes without a Neighboring Tumor-Suppressor Gene Are More Prone to Amplification.

ABSTRACT: Focal copy number gains or losses are important genomic hallmarks of cancer. The genomic distribution of oncogenes and tumor-suppressor genes (TSG) in relation to focal copy number aberrations is unclear. Our analysis revealed that the mean distance of TSGs from oncogenes was significantly shorter than that of noncancer genes, suggesting that oncogenes and TSGs tend to be in close physical proximity in the human genome. Such relationship was conserved in mouse and drosophila. Pan-cancer analysis using data from The Cancer Genome Atlas indicated that oncogenes without a nearby TSG are more prone to amplification. In conclusion, our study provides evidence for the nonrandom distribution of oncogenes and TSGs across different species. Our data also support that the existence of a neighboring TSG can suppress amplification of an oncogene, shedding new light on a previously unappreciated protective mechanism of TSGs.

SUBMITTER: Wu WK

PROVIDER: S-EPMC5400371 | biostudies-literature | 2017 Apr

REPOSITORIES: biostudies-literature

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Oncogenes without a Neighboring Tumor-Suppressor Gene Are More Prone to Amplification.

Wu William K K WK Li Xiangchun X Wang Xiansong X Dai Rudin Z W RZ Cheng Alfred S L AS Wang Maggie H T MH Kwong Thomas T Chow Tai C TC Yu Jun J Chan Matthew T V MT Wong Sunny H SH

Molecular biology and evolution 20170401 4

Focal copy number gains or losses are important genomic hallmarks of cancer. The genomic distribution of oncogenes and tumor-suppressor genes (TSG) in relation to focal copy number aberrations is unclear. Our analysis revealed that the mean distance of TSGs from oncogenes was significantly shorter than that of noncancer genes, suggesting that oncogenes and TSGs tend to be in close physical proximity in the human genome. Such relationship was conserved in mouse and drosophila. Pan-cancer analysis ...[more]

PMID: 28087780

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Project description:BackgroundSo far, investigators have found numerous tumor suppressor genes (TSGs) and oncogenes (OCGs) that control cell proliferation and apoptosis during cancer development. Furthermore, TSGs and OCGs may act as modulators of transcription factors (TFs) to influence gene regulation. A comprehensive investigation of TSGs, OCGs, TFs, and their joint target genes at the network level may provide a deeper understanding of the post-translational modulation of TSGs and OCGs to TF gene regulation.Methodology/principal findingsIn this study, we developed a novel computational framework for identifying target genes of TSGs and OCGs using TFs as bridges through the integration of protein-protein interactions and gene expression data. We applied this pipeline to ovarian cancer and constructed a three-layer regulatory network. In the network, the top layer was comprised of modulators (TSGs and OCGs), the middle layer included TFs, and the bottom layer contained target genes. Based on regulatory relationships in the network, we compiled TSG and OCG profiles and performed clustering analyses. Interestingly, we found TSGs and OCGs formed two distinct branches. The genes in the TSG branch were significantly enriched in DNA damage and repair, regulating macromolecule metabolism, cell cycle and apoptosis, while the genes in the OCG branch were significantly enriched in the ErbB signaling pathway. Remarkably, their specific targets showed a reversed functional enrichment in terms of apoptosis and the ErbB signaling pathway: the target genes regulated by OCGs only were enriched in anti-apoptosis and the target genes regulated by TSGs only were enriched in the ErbB signaling pathway.Conclusions/significanceThis study provides the first comprehensive investigation of the interplay of TSGs and OCGs in a regulatory network modulated by TFs. Our application in ovarian cancer revealed distinct regulatory patterns of TSGs and OCGs, suggesting a competitive regulatory mechanism acting upon apoptosis and the ErbB signaling pathway through their specific target genes.

Dataset Information

Oncogenes without a Neighboring Tumor-Suppressor Gene Are More Prone to Amplification.

Publications

Oncogenes without a Neighboring Tumor-Suppressor Gene Are More Prone to Amplification.

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