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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.
People with Lynch syndrome should be offered daily aspirin, which roughly halves bowel cancer risk with a delayed and durable effect. Whether a lower dose (as tested in CAPP3) is as effective, and whether the finding extends to the general population, are separate questions.
The first demonstration that HER2 is actionable in colorectal cancer, and the trial that defined the colorectal-specific HER2 scoring criteria every later trial has used.
The CMS framework organises colorectal cancer biology and trial stratification; BRAF V600E tumours cluster in CMS1, and CMS4's shorter survival and stromal signalling are targets of ongoing research.
Every screening programme rests on this paper: if cancer arrives through a polyp that takes years to progress, then finding and removing polyps prevents cancer rather than merely catching it early.
Shares Genetic alterations during colorectal-tumor development, APC, SMAD4, Chromosomal instability & aneuploidy.
Shares Somatic mutations from exome and genome sequencing (WXS, WGS), ARID1A, SMAD4, Wnt / β-catenin.
Shares TCF7L2, APC, Wnt / β-catenin, Nature.
Shares APC, SMAD4, Colorectal cancer (KEGG map), Wnt / β-catenin.
Shares ARID1A, SMAD4, Broad Institute of MIT and Harvard, RNA sequencing & expression profiling.
Shares Somatic mutations from exome and genome sequencing (WXS, WGS), Broad Institute of MIT and Harvard, Nature, DNA methylation profiling.
Shares Somatic mutations from exome and genome sequencing (WXS, WGS), ARID1A, SMAD4, Nature.
Shares Chromosomal instability & aneuploidy, Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Mismatch repair & microsatellite instability, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR).