Results: Patient with colorectal cancer and a somatic (tumour) mismatch repair (MMR) deficiency

A 76-year-old woman is diagnosed with localised colorectal cancer and undergoes a right hemicolectomy. There is no significant family history of cancer. Tumour pathology reveals a poorly differentiated adenocarcinoma, pT3N0M0 with clear margins and no lymphovascular invasion.

Somatic (tumour) testing for mismatch repair (MMR) deficiency via immunohistochemistry reveals loss of MLH1 and PMS2. A multi-target massively parallel sequencing (sometimes called next-generation sequencing) panel performed on tumour-derived DNA identifies the somatic variant BRAF:c.1799T>G (p.Val600Gly) (V600E). This suggests sporadic MMR deficiency.

• About 15% of sporadic colorectal cancers exhibit MMR deficiency (usually with associated microsatellite instability). The vast majority of these cases are related to MLH1 promoter hypermethylation.
• Any atypical MMR immunohistochemistry staining or microsatellite instability results should trigger further genomic investigations.
  • If the MLH1 immunohistochemistry result demonstrates MLH1 loss or if microsatellite testing indicates an MSI-high result, BRAF sequencing should be undertaken as the next step.
    • The detection of a pathogenic BRAF variant (usually BRAF c.1799T>A (p.Val600Glu) (V600E), as is the case in this scenario) is suggestive of sporadic MMR deficiency due to hypermethylation of the MLH1 promoter. Further testing is not typically indicated unless clinical suspicion of an underlying heritable risk factor exists (for example, the patient is young or there is a strong family history of cancer).
    • While the presence of a pathogenic BRAF variant is strongly suggestive of MLH1 promoter hypermethylation, the absence of such variants does not exclude this as an underlying mechanism of MMR deficiency. If no BRAF variants are identified, formal testing to check for MLH1 promoter hypermethylation should be performed, as approximately one third of tumours with MLH1 promoter hypermethylation will not have an associated somatic BRAF variant.
      • If MLH1 promoter hypermethylation is detected in tumour-derived DNA, no further testing is indicated.
      • If neither MLH1 promoter hypermethylation nor a somatic (tumour) BRAF pathogenic variant is identified in a tumour demonstrating MLH1 or PMS2 deficiency, testing of constitutional (germline) DNA to check for heritable MMR gene variants (Lynch syndrome) should be undertaken.
  • If no genetic aetiology to explain the mismatch repair deficiency is detected after these steps, further tumour-based testing may be required, after consultation with clinical genetics.
• BRAF variant status is consistently associated with poor prognosis in multiple retrospective studies.
• Targeting BRAF (for example, with encorafenib and cetuximab with chemotherapy) leads to improved survival in these patients in the metastatic setting.

Management of the current cancer

• In a patient with an intermediate-risk stage II colorectal cancer, sporadic MMR deficiency indicates that there would be no benefit from adjuvant chemotherapy with 5-fluorouracil.
  • This is only relevant for intermediate-risk stage II colorectal cancer. Patients with stage III colorectal cancer are usually offered adjuvant chemotherapy regardless of MMR status.
• If the patient develops metastatic disease in the future, immune checkpoint inhibitor therapy may be considered, given documented MMR deficiency.

For clinicians

• European Society for Medical Oncology (ESMO): Clinical practice guidelines: Localised colon cancer
• NHS England: National Genomic Test Directory
• NICE: Molecular testing strategies for Lynch syndrome in people with colorectal cancer

References:

• Elez E, Yoshino T, Shen L and others. ‘Encorafenib, Cetuximab, and mFOLFOX6 in BRAF-Mutated Colorectal Cancer‘. New England Journal of Medicine 2025: volume 392, issue 24, pages 2425–2437. DOI: 10.1056/NEJMoa2501912
• McVeigh TP, Monahan KJ, Christopher J, and others. ‘UKCGG dMMR Consensus Meeting Attendees. Extent of investigation and management of cases of ‘unexplained’ mismatch repair deficiency (u-dMMR): a UK Cancer Genetics Group consensus‘. Journal of Medical Genetics 2024: volume 61, issue 7, pages 707–715. DOI: 10.1136/jmg-2024-109886

For patients

• Macmillan Cancer Support: Bowel cancer (PDF, 13 pages)