Results: Patient with colorectal cancer – somatic MMR deficiency identified

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 MMR deficiency via immunohistochemistry (IHC) reveals loss of MLH1 and PSM2. A multi-target next-generation sequencing (NGS) panel confirms that the tumour has a BRAF V600E mutation. This suggests sporadic MMR deficiency.

Management of the current cancer

• In a patient such as this with an intermediate risk stage 2 colorectal cancer, sporadic MMR deficiency indicates that there would be no benefit from adjuvant chemotherapy with 5-fluorouracil.
  • Note: this is only relevant for intermediate risk stage 2 colorectal cancer. Higher stages of localised colorectal cancer warrant adjuvant chemotherapy regardless of MMR status, and MMR deficiency in the metastatic setting would be an indication to consider immunotherapy.
• All abnormal MMR or MSI results should trigger further genomic investigations.
  • If the MLH1 immunohistochemistry result or microsatellite testing is abnormal, a BRAF V600E test should be checked via the multitarget NGS panel.
    • If a pathogenic BRAF variant is detected (as in this case), this is suggestive of sporadic MMR deficiency, and no further testing is indicated.
    • 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, consistent with sporadic MLH1 promoter hypermethylation, no further testing is indicated.
      • If neither MLH1 promoter hypermethylation nor a somatic BRAF pathogenic variant is identified in a tumour demonstrating MLH1/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).

For clinicians

• ESMO: Clinical practice guidelines – localised colon cancer
• NHS England: National Genomic Test Directory and eligibility criteria
• NICE: Molecular testing strategies for Lynch syndrome in people with colorectal cancer

For patients

Macmillan: Bowel cancer information