title: A map of human cancer signaling.
abstract: We conducted a comprehensive analysis of a manually curated human signaling network containing 1634 nodes and 5089 signaling regulatory relations by integrating cancer-associated genetically and epigenetically altered genes. We find that cancer mutated genes are enriched in positive signaling regulatory loops, whereas the cancer-associated methylated genes are enriched in negative signaling regulatory loops. We further characterized an overall picture of the cancer-signaling architectural and functional organization. From the network, we extracted an oncogene-signaling map, which contains 326 nodes, 892 links and the interconnections of mutated and methylated genes. The map can be decomposed into 12 topological regions or oncogene-signaling blocks, including a few 'oncogene-signaling-dependent blocks' in which frequently used oncogene-signaling events are enriched. One such block, in which the genes are highly mutated and methylated, appears in most tumors and thus plays a central role in cancer signaling. Functional collaborations between two oncogene-signaling-dependent blocks occur in most tumors, although breast and lung tumors exhibit more complex collaborative patterns between multiple blocks than other cancer types. Benchmarking two data sets derived from systematic screening of mutations in tumors further reinforced our findings that, although the mutations are tremendously diverse and complex at the gene level, clear patterns of oncogene-signaling collaborations emerge recurrently at the network level. Finally, the mutated genes in the network could be used to discover novel cancer-associated genes and biomarkers.
authors: Computational Chemistry and Biology Group, Biotechnology Research Institute, National Research Council Canada, Montreal, QC, Canada.
authors: Qinghua
authors: Q
authors: Cui
authors: Yun
authors: Y
authors: Ma
authors: Maria
authors: M
authors: Jaramillo
authors: Hamza
authors: H
authors: Bari
authors: Arif
authors: A
authors: Awan
authors: Song
authors: S
authors: Yang
authors: Simo
authors: S
authors: Zhang
authors: Lixue
authors: L
authors: Liu
authors: Meng
authors: M
authors: Lu
authors: Maureen
authors: M
authors: O'Connor-McCourt
authors: Enrico O
authors: EO
authors: Purisima
authors: Edwin
authors: E
authors: Wang
mesh_terms: D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000235:genetics; D016208:Databases, Factual; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D053208:Kaplan-Meier Estimate; D008954:Models, Biological; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000502:physiology*; D009369:Neoplasms / Q000235:genetics / Q000401:mortality / Q000503:physiopathology*; D015513:Oncogene Proteins / Q000502:physiology; D016016:Proportional Hazards Models; D015398:Signal Transduction / Q000235:genetics / Q000502:physiology*
chemical_list: D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D015513:Oncogene Proteins