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. National Institutes of Health (U.S.) (Grant U24CA143799) National Institutes of Health (U.S.) (Grant U24CA143835) National Institutes of Health (U.S.) (Grant U24CA143840) National Institutes of Health (U.S.) (Grant U24CA143843) National Institutes of Health (U.S.) (Grant U24CA143845) National Institutes of Health (U.S.) (Grant U24CA143848) National Institutes of Health (U.S.) (Grant U24CA143858) National Institutes of Health (U.S.) (Grant U24CA143866) National Institutes of Health (U.S.) (Grant U24CA143867) National Institutes of Health (U.S.) (Grant U24CA143882) National Institutes of Health (U.S.) (Grant U24CA143883) National Institutes of Health (U.S.) (Grant U24CA144025) National Institutes of Health (U.S.) (Grant U54HG003067) National Institutes of Health (U.S.) (Grant U54HG003079) National Institutes of Health (U.S.) (Grant U54HG003273)
