{"entity":{"id":"paper-tcga-colorectal-comprehensive-characterization-nature-2012","kind":"paper","name":"Comprehensive molecular characterization of human colon and rectal cancer","aka":[],"tldr":"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.","summary":"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.\n\nDeposited as coadread_tcga_pub (276 samples) and, re-analysed, as coadread_tcga_pan_can_atlas_2018 (594 samples) on cBioPortal.","asOf":"2026-09-24","links":[{"label":"Cancer Genome Atlas Network, Nature 2012: comprehensive molecular characterisation of 276 colon and rectal cancers","url":"https://doi.org/10.1038/nature11252"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/22810696/"},{"label":"cBioPortal study coadread_tcga_pub (TCGA, Nature 2012; 276 samples, 224 sequenced, 257 with copy number)","url":"https://www.cbioportal.org/study/summary?id=coadread_tcga_pub"},{"label":"cBioPortal study coadread_tcga_pan_can_atlas_2018 (TCGA PanCancer Atlas colorectal; 594 samples, 534 sequenced, 592 with copy number)","url":"https://www.cbioportal.org/study/summary?id=coadread_tcga_pan_can_atlas_2018"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["wes-wgs","rna-seq","methylation-profiling"],"targets":["apc","tp53","kras","smad4","pik3ca","arid1a","sox9","amer1","her2","myc-gene"],"drugs":[],"companies":[],"institutions":["nci","broad-institute"],"pathways":["colorectal-cancer-signalling","wnt","chromosomal-instability","mismatch-repair-msi","myc"],"terms":["msi","somatic-mutations-wxs-wgs"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature"],"dependsOn":[],"notes":[],"journal":"Nature","year":2012,"doi":"10.1038/nature11252","pmid":"22810696","authors":"Cancer Genome Atlas Network.","paperType":"translational","findings":["16% hypermutated: three-quarters MSI with MLH1 silencing, one-quarter somatic mismatch repair or POLE mutation.","24 significantly mutated genes, adding ARID1A, SOX9 and FAM123B to the known drivers.","ERBB2 and IGF2 amplification; WNT signalling altered in 93% of tumours."],"whatItMeans":"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.","caveats":["Surgical resections, so metastatic disease and its enrichment for microsatellite-stable tumours are under-represented.","The public deposit differs from the analysed set; the PanCancer Atlas re-analysis covers 594 samples.","Expression subtypes from this paper were superseded by the consensus molecular subtypes."],"changedPractice":false,"participants":276},"route":"/key-papers/paper-tcga-colorectal-comprehensive-characterization-nature-2012/","neighbours":{"cancer":[{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"}],"technology":[{"id":"methylation-profiling","kind":"technology","name":"DNA methylation profiling","route":"/technologies/methylation-profiling/"},{"id":"rna-seq","kind":"technology","name":"RNA sequencing & expression profiling","route":"/technologies/rna-seq/"},{"id":"wes-wgs","kind":"technology","name":"Whole-exome & whole-genome sequencing","route":"/technologies/wes-wgs/"}],"target":[{"id":"amer1","kind":"target","name":"AMER1","route":"/targets/amer1/"},{"id":"apc","kind":"target","name":"APC","route":"/targets/apc/"},{"id":"arid1a","kind":"target","name":"ARID1A","route":"/targets/arid1a/"},{"id":"fbxw7","kind":"target","name":"FBXW7","route":"/targets/fbxw7/"},{"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":"myc-gene","kind":"target","name":"MYC","route":"/targets/myc-gene/"},{"id":"pik3ca","kind":"target","name":"PIK3CA / PI3K-alpha","route":"/targets/pik3ca/"},{"id":"smad4","kind":"target","name":"SMAD4","route":"/targets/smad4/"},{"id":"sox9","kind":"target","name":"SOX9","route":"/targets/sox9/"},{"id":"tcf7l2","kind":"target","name":"TCF7L2","route":"/targets/tcf7l2/"},{"id":"tp53","kind":"target","name":"TP53","route":"/targets/tp53/"}],"institution":[{"id":"broad-institute","kind":"institution","name":"Broad Institute of MIT and Harvard","route":"/institutions/broad-institute/"},{"id":"nci","kind":"institution","name":"National Cancer Institute (NIH)","route":"/institutions/nci/"}],"pathway":[{"id":"chromosomal-instability","kind":"pathway","name":"Chromosomal instability & aneuploidy","route":"/pathways/chromosomal-instability/"},{"id":"colorectal-cancer-signalling","kind":"pathway","name":"Colorectal cancer (KEGG map)","route":"/pathways/colorectal-cancer-signalling/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"},{"id":"myc","kind":"pathway","name":"MYC","route":"/pathways/myc/"},{"id":"wnt","kind":"pathway","name":"Wnt / β-catenin","route":"/pathways/wnt/"}],"term":[{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"},{"id":"somatic-mutations-wxs-wgs","kind":"term","name":"Somatic mutations from exome and genome sequencing (WXS, WGS)","route":"/terms/somatic-mutations-wxs-wgs/"}],"journal":[{"id":"nature","kind":"journal","name":"Nature","route":"/journals/nature/"}]}}