# CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer

Source: https://onco.cc/key-papers/paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006/  
OnCo record `paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006` (Key paper). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

## Fields

- Kind: Key paper
- Last checked: 2026-09-24
- Journal: Nature Genetics
- Year: 2006
- DOI: 10.1038/ng1834
- Authors: Weisenberger DJ, Siegmund KD, Campan M, et al.
- 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.
- What it means: 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.

## Sources

- Weisenberger et al., Nat Genet 2006: CIMP underlies sporadic microsatellite instability and tracks BRAF mutation (295 tumours): https://doi.org/10.1038/ng1834
- PubMed: https://pubmed.ncbi.nlm.nih.gov/16804544/

## Connected records

- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)
- technologies: [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [MSI and mismatch-repair testing](https://onco.cc/technologies/msi-mmr-testing/)
- targets: [BRAF](https://onco.cc/targets/braf/), [Mismatch repair proteins (MLH1, MSH2, MSH6, PMS2)](https://onco.cc/targets/mmr/), [MLH1](https://onco.cc/targets/mlh1/)
- pathways: [Epigenetic reprogramming](https://onco.cc/pathways/epigenetic-reprogramming/), [Mismatch repair & microsatellite instability](https://onco.cc/pathways/mismatch-repair-msi/)
- terms: [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/)
- journals: [Nature Genetics](https://onco.cc/journals/nature-genetics/)
- biomarkers: [BRAF V600E (and V600K)](https://onco.cc/biomarkers/braf-v600e/), [dMMR (mismatch repair deficiency by IHC)](https://onco.cc/biomarkers/dmmr-ihc/)

---
JSON: https://onco.cc/api/v1/entities/paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006.json