Combinatorial Patterns of Somatic Mutations in Cancer Chen-Hsiang Yeang Institute for Advanced Study Cancer is a complex process where the abnormalities of many genes are involved. The combinatorial patterns of gene mutations can reveal the functional relations of genes and pathways in cancer formation and possibly identify the targets for treatments. We examine the patterns of somatic gene mutations of cancer from COSMIC, a large-scale database curated by the Sanger Institute. Albeit most frequently mutated genes are well-known oncogenes and tumor suppressors involved in generic processes of cell cycle control, signal transduction and stress response, the "signatures" of gene mutations are heterogeneous across different tissues. Genes participating in different pathways have the tendency of co-mutations, whereas genes participating in the same pathway rarely mutate together. This observation supports the view of tumorigenesis as Darwinian evolution. However, certain combinatorial mutational patterns violate these simple rules and demonstrate variations across tissues. For instance, mutations of genes in Ras and Wnt pathways tend to co-occur in large intestine, but are mutually exclusive in pancreas and small intestine. In addition, the observed mutational patterns suggest candidates of new co-sequencing targets that can either reveal novel patterns or validate the predictions deduced from existing patterns. The combinatorial mutational patterns inferred from COSMIC provide guiding information for the ongoing cancer genome projects. Joint work with Arnold Levine at the Institute for Advanced Study.
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