Comprehensive molecular characterization of human colon and rectal cancer

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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 andMLH1silencing, 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 expectedAPC, TP53, SMAD4, PIK3CAandKRASmutations, we found frequent mutations inARID1A, SOX9 and FAM123B.Recurrent copy-number alterations include potentially drug-targetable amplifications ofERBB2and newly discovered amplification ofIGF2. Recurrent chromosomal translocations include the fusion ofNAV2and WNT pathway memberTCF7L1. Integrative analyses suggest new markers for aggressive colorectal carcinoma and an important role forMYC-directed transcriptional activation and repression.

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