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 regula...
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Veröffentlicht in: | Molecular systems biology 2007, Vol.3 (1), p.152-n/a |
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Zusammenfassung: | 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.
Synopsis
Cancer is largely a genetic disease that is caused by acquiring genomic alterations in cells. It is proposed that a malignant tumor arises from a single cell, which undergoes a series of evolutionary processes of genetic or epigenetic changes and selections so that a cell within the population can acquire additional selective advantages, resulting in progressive clonal expansion (Nowell,
1976
). Enormous efforts have been made over the past few decades to identify gene mutations that are causally implicated in human cancer. Recently, a whole‐genome or large‐scale efforts toward the identification of genetic and epigenetic changes in tumor samples have been conducted (Stephens
et al
,
2005
; Sjoblom
et al
,
2006
; Greenman
et al
,
2007
; Ohm
et al
,
2007
; Schlesinger
et al
,
2007
; Thomas
et al
,
2007
; Widschwendter
et al
,
200 |
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ISSN: | 1744-4292 1744-4292 |
DOI: | 10.1038/msb4100200 |