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The Cancer Genome Atlas read 276 bowel cancers end to end and found that colon and rectal tumours are genetically the same disease, that one in six is hypermutated, and that a few carry a HER2 amplification that a drug could hit.
The Cancer Genome Atlas Network conducted a genome-scale analysis of 276 colorectal samples, analysing exome sequence, DNA copy number, promoter methylation and messenger RNA and microRNA expression, with 97 of the samples also undergoing low-depth whole-genome sequencing.
In total 16 percent of the carcinomas were 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 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 mutations, the network found frequent mutations in ARID1A, SOX9 and FAM123B. Recurrent copy-number alterations included potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2; recurrent chromosomal translocations included the fusion of NAV2 and the WNT pathway member TCF7L1. Integrative analyses suggested new markers for aggressive disease and an important role for MYC-directed transcriptional activation and repression.
The paper that put HER2 on the colorectal map (HERACLES, MOUNTAINEER and DESTINY-CRC follow from it) and that showed the hypermutated group, later the immunotherapy-responsive group, is defined by two distinct mechanisms.
Chemoprevention in a defined high-risk group is possible, and aspirin is now offered to Lynch syndrome carriers in UK practice; the CaPP3 dose-finding study asks whether a much smaller dose does the same.
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 poor prognosis 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 Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study, Genetic alterations during colorectal-tumor development, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation, Colorectal cancer and the tag colorectal-evidence.
Shares Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES), HER2-amplified colorectal cancer, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation, HER2 and the tag colorectal-evidence.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Whole-exome & whole-genome sequencing, Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Mismatch-repair deficient (MSI-high) colorectal cancer and the tag colorectal-evidence.
Shares APC, Nature, Whole-exome & whole-genome sequencing, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation and the tag colorectal-evidence.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Mismatch-repair deficient (MSI-high) colorectal cancer, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation and the tag colorectal-evidence.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Mismatch-repair deficient (MSI-high) colorectal cancer, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation and the tag colorectal-evidence.
Shares Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2), Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR), Mismatch-repair deficient (MSI-high) colorectal cancer, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation and the tag colorectal-evidence.
Shares Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES), HER2-amplified colorectal cancer, Colorectal cancer roadmap: from the adenoma-carcinoma sequence and the first screening trials to total mesorectal excision, oxaliplatin, RAS testing, immunotherapy for mismatch repair-deficient disease, ctDNA-guided treatment and organ preservation, HER2 and the tag colorectal-evidence.