{"entity":{"id":"paper-tcga-colon-rectal-molecular-characterization-nature-2012","kind":"paper","name":"Comprehensive molecular characterization of human colon and rectal cancer","aka":[],"tldr":"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.","summary":"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.\n\nIn 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.","asOf":"2026-09-24","links":[{"label":"Nature 2012","url":"https://doi.org/10.1038/nature11252"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22810696/"},{"label":"Europe PMC full text (PMC3401966)","url":"https://europepmc.org/article/MED/22810696"}],"tags":["colorectal-evidence"],"related":["paper-cms-guinney-nat-med-2015","paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988"],"cancers":["colorectal","colon-cancer","rectal-cancer","msi-high-colorectal","her2-amplified-colorectal"],"sections":[],"technologies":["wes-wgs","ngs"],"targets":["apc","tp53","kras","smad4","her2","myc"],"drugs":[],"companies":[],"institutions":[],"pathways":["wnt","ras-mapk"],"terms":["msi","mmr"],"trials":[],"people":[],"bottlenecks":["b-tumor-heterogeneity"],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2012,"doi":"10.1038/nature11252","pmid":"22810696","authors":"Cancer Genome Atlas Network.","paperType":"basic","findings":["16 percent of colorectal carcinomas were hypermutated; three-quarters of those had high microsatellite instability with MLH1 silencing and one-quarter had mismatch-repair or POLE mutations.","Excluding hypermutated cancers, colon and rectal tumours had considerably similar patterns of genomic alteration.","Twenty-four genes were significantly mutated, including ARID1A, SOX9 and FAM123B alongside APC, TP53, SMAD4, PIK3CA and KRAS.","Potentially drug-targetable amplifications of ERBB2 and newly discovered amplification of IGF2."],"whatItMeans":"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.","caveats":["276 largely untreated primary tumours from one era and mostly one continent; it says nothing about how tumours change under treatment.","Significantly mutated gene lists depend on the background mutation model, and the hypermutated tumours had to be analysed separately for that reason."],"changedPractice":true,"participants":276},"route":"/key-papers/paper-tcga-colon-rectal-molecular-characterization-nature-2012/","neighbours":{"paper":[{"id":"paper-burn-capp2-aspirin-lynch-syndrome-lancet-2020","kind":"paper","name":"Cancer prevention with aspirin in hereditary colorectal cancer (Lynch syndrome), 10-year follow-up and registry-based 20-year data in the CAPP2 study","route":"/key-papers/paper-burn-capp2-aspirin-lynch-syndrome-lancet-2020/"},{"id":"paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016","kind":"paper","name":"Dual-targeted therapy with trastuzumab and lapatinib in treatment-refractory, KRAS codon 12/13 wild-type, HER2-positive metastatic colorectal cancer (HERACLES)","route":"/key-papers/paper-sartore-bianchi-heracles-trastuzumab-lapatinib-lancet-oncol-2016/"},{"id":"paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988","kind":"paper","name":"Genetic alterations during colorectal-tumor development","route":"/key-papers/paper-vogelstein-genetic-alterations-colorectal-tumor-development-nejm-1988/"},{"id":"paper-cms-guinney-nat-med-2015","kind":"paper","name":"The consensus molecular subtypes of colorectal cancer","route":"/key-papers/paper-cms-guinney-nat-med-2015/"}],"cancer":[{"id":"colon-cancer","kind":"cancer","name":"Colon cancer (adenocarcinoma of the colon)","route":"/cancers/colon-cancer/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"her2-amplified-colorectal","kind":"cancer","name":"HER2-amplified colorectal cancer","route":"/cancers/her2-amplified-colorectal/"},{"id":"msi-high-colorectal","kind":"cancer","name":"Mismatch-repair deficient (MSI-high) colorectal cancer","route":"/cancers/msi-high-colorectal/"},{"id":"rectal-cancer","kind":"cancer","name":"Rectal cancer","route":"/cancers/rectal-cancer/"}],"technology":[{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"term":[{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"ngs","kind":"term","name":"Next-generation sequencing (NGS)","route":"/terms/ngs/"}],"target":[{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"her2","kind":"target","name":"HER2","route":"/targets/her2/"},{"id":"kras","kind":"target","name":"KRAS","route":"/targets/kras/"},{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"pathway":[{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"ras-mapk","kind":"pathway","name":"RAS / RAF / MEK / ERK (MAPK)","route":"/pathways/ras-mapk/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"bottleneck":[{"id":"b-tumor-heterogeneity","kind":"bottleneck","name":"Tumour heterogeneity and clonal evolution","route":"/bottlenecks/b-tumor-heterogeneity/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}],"roadmap":[{"id":"colorectal-roadmap","kind":"roadmap","name":"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","route":"/roadmaps/colorectal-roadmap/"}]}}