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The Cancer Genome Atlas read the DNA, copy number, methylation and gene activity of 276 bowel cancers, found that one in six carries an enormous number of mutations, and showed that once those are set aside colon and rectal cancers look the same.
A genome-scale analysis of 276 samples combined exome sequence, DNA copy number, promoter methylation, messenger RNA and microRNA expression, with low-coverage whole-genome sequencing in 97. Sixteen per cent of colorectal carcinomas were hypermutated: three-quarters of those had the expected high microsatellite instability, usually with hypermethylation and MLH1 silencing, and one-quarter had somatic mismatch repair gene and polymerase epsilon (POLE) mutations. Excluding the hypermutated cancers, colon and rectum cancers had considerably similar patterns of genomic alteration. Twenty-four genes were significantly mutated: in addition to the expected APC, TP53, SMAD4, PIK3CA and KRAS, frequent mutations were found in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations included potentially drug-targetable amplification of ERBB2 and newly discovered amplification of IGF2; recurrent translocations included a fusion of NAV2 with the WNT pathway member TCF7L1. Integrative analysis suggested new markers of aggressive disease and an important role for MYC-directed transcriptional activation and repression.
Deposited as coadread_tcga_pub (276 samples) and, re-analysed, as coadread_tcga_pan_can_atlas_2018 (594 samples) on cBioPortal.
It is the reference description of the disease and the source of the hypermutated split that decides who gets immunotherapy; it also put HER2 on the colorectal map as a drug target.
Shares APC, SMAD4, MYC, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2).
Shares TCF7L2, APC, Wnt / β-catenin, Nature.
Shares Somatic mutations from exome and genome sequencing (WXS, WGS), ARID1A, SMAD4, Nature.
Shares APC, Chromosomal instability & aneuploidy, SMAD4, Colorectal cancer (KEGG map).
Shares Somatic mutations from exome and genome sequencing (WXS, WGS), ARID1A, SMAD4, Wnt / β-catenin.
Shares ARID1A, SMAD4, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).
Shares MYC, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Wnt / β-catenin.
Shares APC, Chromosomal instability & aneuploidy, SMAD4, Colorectal cancer (KEGG map).