A map of human cancer signaling.
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.
Cui
Qinghua
Q
Computational Chemistry and Biology Group, Biotechnology Research Institute, National Research Council Canada, Montreal, QC, Canada.
Ma
Yun
Y
Jaramillo
Maria
M
Bari
Hamza
H
Awan
Arif
A
Yang
Song
S
Zhang
Simo
S
Liu
Lixue
L
Lu
Meng
M
O'Connor-McCourt
Maureen
M
Purisima
Enrico O
EO
Wang
Edwin
E
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*
D004273:DNA, Neoplasm; D009363:Neoplasm Proteins; D015513:Oncogene Proteins