{"entity":{"id":"paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","kind":"paper","name":"CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer","aka":[],"tldr":"Some bowel cancers switch off large numbers of genes by chemical tagging. This study settled a long argument by showing that those tumours are a genuinely distinct group, that they nearly all carry a BRAF mutation, and that they are where sporadic loss of the DNA spell-checker comes from.","summary":"A systematic, stepwise screen of 195 CpG island methylation markers using MethyLight technology was performed on 295 primary human colorectal tumours, involving 16,785 separate quantitative analyses. CIMP-positive tumours were shown to represent a distinct subset, encompassing almost all cases of tumours with BRAF mutation (odds ratio 203). Sporadic cases of mismatch repair deficiency occurred almost exclusively as a consequence of CIMP-associated methylation of MLH1. The authors proposed a five-marker panel to classify CIMP-positive tumours.","asOf":"2026-09-24","links":[{"label":"Weisenberger et al., Nat Genet 2006: CIMP underlies sporadic microsatellite instability and tracks BRAF mutation (295 tumours)","url":"https://doi.org/10.1038/ng1834"},{"label":"PubMed","url":"https://pubmed.ncbi.nlm.nih.gov/16804544/"}],"tags":[],"related":[],"cancers":["colorectal"],"sections":[],"technologies":["methylation-profiling"],"targets":["braf","mlh1","mmr"],"drugs":[],"companies":[],"institutions":[],"pathways":["epigenetic-reprogramming","mismatch-repair-msi"],"terms":["msi","lynch-syndrome"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":[],"journals":["nature-genetics"],"dependsOn":[],"notes":[],"journal":"Nature Genetics","year":2006,"doi":"10.1038/ng1834","pmid":"16804544","authors":"Weisenberger DJ, Siegmund KD, Campan M, et al.","paperType":"translational","findings":["CIMP-positive tumours are a distinct subset encompassing almost all BRAF-mutant cancers (odds ratio 203).","Sporadic mismatch repair deficiency arises almost exclusively through CIMP-associated MLH1 methylation.","A five-marker classification panel was proposed."],"whatItMeans":"It is the molecular definition of the serrated route and the reason BRAF V600E is used as a practical surrogate for sporadic rather than inherited MLH1 loss.","caveats":["Marker panels for CIMP still differ between laboratories, so reported CIMP rates vary.","CIMP is not itself a treatment decision anywhere."],"changedPractice":false,"participants":295},"route":"/key-papers/paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006/","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":"msi-mmr-testing","kind":"technology","name":"MSI and mismatch-repair testing","route":"/technologies/msi-mmr-testing/"}],"target":[{"id":"braf","kind":"target","name":"BRAF","route":"/targets/braf/"},{"id":"mmr","kind":"target","name":"Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)","route":"/targets/mmr/"},{"id":"mlh1","kind":"target","name":"MLH1","route":"/targets/mlh1/"}],"pathway":[{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","route":"/pathways/epigenetic-reprogramming/"},{"id":"mismatch-repair-msi","kind":"pathway","name":"Mismatch repair & microsatellite instability","route":"/pathways/mismatch-repair-msi/"}],"term":[{"id":"lynch-syndrome","kind":"term","name":"Lynch syndrome","route":"/terms/lynch-syndrome/"},{"id":"msi","kind":"term","name":"Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)","route":"/terms/msi/"}],"journal":[{"id":"nature-genetics","kind":"journal","name":"Nature Genetics","route":"/journals/nature-genetics/"}],"biomarker":[{"id":"braf-v600e","kind":"biomarker","name":"BRAF V600E (and V600K)","route":"/biomarkers/braf-v600e/"},{"id":"dmmr-ihc","kind":"biomarker","name":"dMMR (mismatch repair deficiency by IHC)","route":"/biomarkers/dmmr-ihc/"}]}}