# Mismatch-repair deficient (MSI-high) colorectal cancer

Source: https://onco.cc/cancers/msi-high-colorectal/  
OnCo record `msi-high-colorectal` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

Mismatch-repair deficient bowel cancer has lost its DNA spell-checker, so it carries thousands of mutations that the immune system can recognise. Immunotherapy alone controls most metastatic cases for years and makes most localised tumours disappear before surgery, sometimes so completely that no surgery is needed.

## Summary

Mismatch-repair deficiency arises when MLH1, MSH2, MSH6 or PMS2 is lost, either by sporadic MLH1 promoter methylation (typically right-sided, in older women, often with BRAF V600E) or by a germline mutation in Lynch syndrome, which is why every colorectal cancer is now tested by immunohistochemistry or microsatellite analysis at diagnosis. The tumours accumulate tens of thousands of frameshift mutations, produce abundant neoantigens and are infiltrated by T cells held in check by PD-1; they have a better prognosis when localised and do not benefit from fluorouracil alone as adjuvant therapy.

In metastatic disease KEYNOTE-177 (2020) showed that pembrolizumab alone doubled progression-free survival against chemotherapy (16.5 versus 8.2 months), with 54.8 percent of patients alive at five years and a median survival of 77.5 months; CheckMate 8HW (2024) showed that nivolumab plus ipilimumab cut progression by 79 percent against chemotherapy (median progression-free survival 54.1 versus 5.9 months) and beat nivolumab alone, and the combination was approved first line in April 2025. About a third of patients still progress early, often because of pMMR misclassification, JAK1 or B2M loss or immune-excluded biology.

In localised disease four weeks of neoadjuvant nivolumab and ipilimumab produced pathological complete response in 68 percent of colon cancers in NICHE-2 with no recurrence at three years; the ATOMIC phase 3 trial (2025) showed that adding atezolizumab to adjuvant FOLFOX improves disease-free survival in stage III disease; and in rectal cancer six months of dostarlimab produced a clinical complete response in every patient treated, allowing surgery and radiotherapy to be omitted. For Lynch carriers, colonoscopy every one to two years and daily aspirin (CAPP2) prevent cancers, and frameshift-neoantigen vaccines are in trials.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: dMMR colorectal cancer; MSI-H colorectal cancer; Microsatellite unstable colorectal cancer; Lynch-associated colorectal cancer; Hypermutated colorectal cancer
- Tags: subtype-page
- Group: gastrointestinal
- Burden: About 15 percent of localised and 5 percent of metastatic colorectal cancers have lost DNA mismatch repair, most often through methylation of the MLH1 gene in right-sided tumours of older women and, in about a fifth, through inherited Lynch syndrome.
- Subtypes: Sporadic mismatch-repair deficient (MLH1 promoter methylation, right-sided, often BRAF V600E); Lynch syndrome (germline MLH1, MSH2, MSH6, PMS2 or EPCAM); Localised dMMR colon cancer (neoadjuvant or adjuvant immunotherapy); dMMR rectal cancer (non-operative management with a PD-1 antibody); Metastatic MSI-high colorectal cancer (first-line checkpoint blockade)
- Biomarkers: Mismatch repair immunohistochemistry (MLH1, MSH2, MSH6, PMS2); Microsatellite instability by PCR or sequencing; MLH1 promoter methylation and BRAF V600E (sporadic versus Lynch); Germline testing of mismatch repair genes; Tumour mutational burden; Circulating tumour DNA after curative treatment

## Standard of care

- Metastatic, first line: Pembrolizumab alone (KEYNOTE-177) or nivolumab plus ipilimumab (CheckMate 8HW); chemotherapy only if immunotherapy is contraindicated. ([Pembrolizumab](https://onco.cc/drugs/pembrolizumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/), [CheckMate 8HW](https://onco.cc/trials/checkmate-8hw/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/))
- Localised colon cancer: Neoadjuvant nivolumab plus ipilimumab for locally advanced tumours (NICHE-2) where available; surgery; adjuvant FOLFOX plus atezolizumab for stage III (ATOMIC); no fluoropyrimidine alone. ([NICHE-2](https://onco.cc/trials/niche-2/), [ATOMIC (Alliance A021502)](https://onco.cc/trials/atomic/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/))
- Rectal cancer: Six months of dostarlimab or another PD-1 antibody with non-operative management for complete responders (AZUR-1). ([Dostarlimab](https://onco.cc/drugs/dostarlimab/), [AZUR-1](https://onco.cc/trials/azur-1/), [Organ preservation (watch-and-wait, bladder-sparing, larynx preservation)](https://onco.cc/terms/organ-preservation/), [Clinical complete response (cCR)](https://onco.cc/terms/clinical-complete-response/))
- Lynch syndrome carriers: Colonoscopy every one to two years from age 25 (earlier for MLH1 and MSH2), daily aspirin (CAPP2), cascade germline testing of relatives, hysterectomy and oophorectomy after childbearing for women. ([Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Aspirin](https://onco.cc/drugs/aspirin/), [Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)](https://onco.cc/technologies/colorectal-screening/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Chemoprevention & risk-reducing surgery](https://onco.cc/technologies/chemoprevention/))

## State of the art

- First-line immunotherapy without chemotherapy in metastatic disease, with more than half of patients alive at five years in KEYNOTE-177.
- Neoadjuvant checkpoint blockade produces pathological complete response in most localised colon cancers (NICHE-2).
- Rectal cancer can be cured with a PD-1 antibody alone, without surgery or radiotherapy.
- Universal mismatch repair testing at diagnosis finds Lynch families.

## Open problems

- A third of metastatic patients progress early on immunotherapy and the resistance mechanisms are only partly understood.
- Whether surgery can be omitted after complete response in colon, as in rectal, cancer is untested.
- WRN helicase inhibitors, a synthetic-lethal approach, are in early trials.
- Lynch carriers still get cancers between colonoscopies; a preventive vaccine is in randomised testing.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Microsatellite_instability
- Wikipedia: https://en.wikipedia.org/wiki/Microsatellite_instability
- NCCN Guidelines: Colon Cancer: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1428

## Connected records

- technologies: [Chemoprevention & risk-reducing surgery](https://onco.cc/technologies/chemoprevention/), [Colorectal cancer screening (colonoscopy, FIT, stool DNA, blood)](https://onco.cc/technologies/colorectal-screening/), [Germline (hereditary) testing](https://onco.cc/technologies/germline-testing/), [Histopathology & immunohistochemistry](https://onco.cc/technologies/histopathology-ihc/), [Immune checkpoint inhibitors](https://onco.cc/technologies/checkpoint-inhibitor/)
- targets: [BRAF](https://onco.cc/targets/braf/), [CTLA-4](https://onco.cc/targets/ctla4/), [PD-1](https://onco.cc/targets/pd1/), [WRN helicase (MSI-high cancers)](https://onco.cc/targets/wrn/)
- drugs: [Aspirin](https://onco.cc/drugs/aspirin/), [Atezolizumab](https://onco.cc/drugs/atezolizumab/), [Cadonilimab](https://onco.cc/drugs/cadonilimab/), [Dostarlimab](https://onco.cc/drugs/dostarlimab/), [EIK1005](https://onco.cc/drugs/eik1005/), [FOLFOX (5-FU, leucovorin, oxaliplatin)](https://onco.cc/drugs/folfox/), [Ipilimumab](https://onco.cc/drugs/ipilimumab/), [Nivolumab](https://onco.cc/drugs/nivolumab/), [Pembrolizumab](https://onco.cc/drugs/pembrolizumab/)
- pathways: [Colorectal cancer (KEGG map)](https://onco.cc/pathways/colorectal-cancer-signalling/)
- terms: [Clinical complete response (cCR)](https://onco.cc/terms/clinical-complete-response/), [Consensus molecular subtypes (CMS1-4)](https://onco.cc/terms/cms-subtypes/), [Lynch syndrome](https://onco.cc/terms/lynch-syndrome/), [Microsatellite instability (MSI-H) / mismatch repair deficiency (dMMR)](https://onco.cc/terms/msi/), [Organ preservation (watch-and-wait, bladder-sparing, larynx preservation)](https://onco.cc/terms/organ-preservation/), [Tumour mutational burden (TMB)](https://onco.cc/terms/tmb/), [Tumour-agnostic (tissue-agnostic) approval](https://onco.cc/terms/tumour-agnostic/)
- trials: [A Study of Dostarlimab in Participants With Untreated Locally Advanced Rectal Cancer in China](https://onco.cc/trials/nct06640049/), [A Study of Neoadjuvant QL1706 in Participants With Untreated dMMR/MSI-H Resectable Colon Cancer](https://onco.cc/trials/nct06686576/), [ATOMIC (Alliance A021502)](https://onco.cc/trials/atomic/), [AZUR-1](https://onco.cc/trials/azur-1/), [CheckMate 8HW](https://onco.cc/trials/checkmate-8hw/), [KEYNOTE-177](https://onco.cc/trials/keynote-177/), [Neoadjuvant/Adjuvant AK104 in Microsatellite Instability-high or Mismatch Repair-deficient, Resectable Colon Cancer](https://onco.cc/trials/nct07412613/), [NICHE-2](https://onco.cc/trials/niche-2/), [Study of Perioperative Dostarlimab in Participants With Untreated T4N0 or Stage III dMMR/MSI-H Resectable Colon Cancer](https://onco.cc/trials/nct05855200/)
- people: [Andrea Cercek](https://onco.cc/people/andrea-cercek/), [Heinz-Josef Lenz](https://onco.cc/people/heinz-josef-lenz/), [Luis A. Diaz Jr.](https://onco.cc/people/luis-diaz/), [Thierry André](https://onco.cc/people/thierry-andre/)
- ideas: [A randomised trial of a shared-antigen vaccine to prevent Lynch syndrome cancers](https://onco.cc/ideas/idea-prev-lynch-frameshift-vaccine-rct/), [Get every Lynch syndrome carrier onto the right dose of aspirin](https://onco.cc/ideas/idea-prev-lynch-aspirin-implementation/), [WRN inhibitors: a second synthetic-lethal win for mismatch-repair cancers](https://onco.cc/ideas/idea-bio1-wrn-msi-programme/)
- cancers: [Colorectal cancer](https://onco.cc/cancers/colorectal/)

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