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Example clinical scenario

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.

Impact of the genomic result

  • 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.
  • All abnormal MMR immunohistochemistry staining or microsatellite instability results should trigger further genomic investigations.
    • If the MLH1 immunohistochemistry result or microsatellite testing is atypical, a BRAF V600E test should be checked via the multi-target massively parallel sequencing panel.
        • The detection of a pathogenic BRAF variant (as is the case in this scenario) is suggestive of sporadic MMR deficiency, and no further testing is 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).
        • If the BRAF V600E test is negative, an MLH1 promoter hypermethylation test should be performed.
          • 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 immunohistochemistry testing indicates loss of MSH2 and/or MSH6, or isolated PMS2 loss, proceed directly to testing of constitutional (germline) DNA for heritable MMR gene variants (Lynch syndrome).
  • BRAF variant status is consistently associated with poor prognosis in multiple retrospective evaluations.

What do you need to do?

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. Stage III colorectal cancer would warrant adjuvant chemotherapy regardless of MMR status.
  • If the patient were to develop metastatic disease in the future, MMR deficiency would be an indication to consider immune checkpoint inhibitor therapy.


For patients

Tagged: Colorectal cancer

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  • Last reviewed: 10/02/2024
  • Next review due: 10/02/2025
  • Authors: Dr Alison Berner
  • Reviewers: Dr Ellen Copson, Dr Amy Frost, Dr Terri McVeigh, Dr Amal Singh