Abstract
Cancer is a complex process in which the abnormalities of many genes
appear to be involved. The combinatorial patterns of gene mutations
may reveal the functional relations between genes and pathways in
tumorigenesis as well as identify targets for treatment. We examined
the patterns of somatic mutations of cancers from Catalog of Somatic
Mutations in Cancer (COSMIC), a large-scale database curated by the
Wellcome Trust Sanger Institute. The frequently mutated genes are
well-known oncogenes and tumor suppressors that are involved in generic
processes of cell-cycle control, signal transduction, and stress
responses. These "signatures" of gene mutations are heterogeneous
when the cancers from different tissues are compared. Mutations in
genes functioning in different pathways can occur in the same cancer
(i.e., co-occur), whereas those in genes functioning in the same
pathway are rarely mutated in the same sample. This observation supports
the view of tumorigenesis as derived from a process like Darwinian
evolution. However, certain combinatorial mutational patterns violate
these simple rules and demonstrate tissue-specific variations. For
instance, mutations of genes in the Ras and Wnt pathways tend to
co-occur in the large intestine but are mutually exclusive in cancers
of the pancreas. The relationships between mutations in different
samples of a cancer can also reveal the temporal orders of mutational
events. In addition, the observed mutational patterns suggest candidates
of new cosequencing targets that can either reveal novel patterns
or validate the predictions deduced from existing patterns. These
combinatorial mutational patterns provide guiding information for
the ongoing cancer genome projects.
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