To characterize
somatic alterations in colorectal carcinoma, we conducted a genome-scale
analysis of 276 samples, analysing exome sequence, DNA copy number, promoter
methylation and messenger RNA and microRNA expression. A subset of these
samples (97) underwent low-depth-of-coverage whole-genome sequencing. In total,
16% of colorectal carcinomas were found to be hypermutated: three-quarters of
these had the expected high microsatellite instability, usually with
hypermethylation and MLH1 silencing, and one-quarter had somatic
mismatch-repair gene and polymerase ε (POLE) mutations. Excluding the hypermutated cancers,
colon and rectum cancers were found to have considerably similar patterns of
genomic alteration. Twenty-four genes were significantly mutated, and in
addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS mutations, we found
frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number
alterations include potentially drug-targetable amplifications of ERBB2 and
newly discovered amplification of IGF2. Recurrent chromosomal translocations include
the fusion of NAV2 and WNT pathway member TCF7L1. Integrative analyses suggest
new markers for aggressive colorectal carcinoma and an important role for
MYC-directed transcriptional activation and repression.
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