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Additional loss of MSH2 and MSH6 expression in sporadic deficient mismatch repair colorectal cancer due to MLH1 promoter hypermethylation
  1. Alice Westwood1,
  2. Amy Glover1,
  3. Gordon Hutchins1,
  4. Caroline Young1,
  5. Scarlet Brockmoeller1,
  6. Rachel Robinson2,
  7. Lisa Worrilow2,
  8. Dave Wallace2,
  9. Kate Rankeillor2,
  10. Julian Adlard2,
  11. Philip Quirke1,
  12. Nicholas West1
  1. 1 Pathology, University of Leeds, Leeds, UK
  2. 2 Genetics Laboratory, Leeds Teaching Hospitals NHS Trust, Leeds, UK
  1. Correspondence to Dr Nicholas West, Pathology, Wellcome Trust Brenner building, University of Leeds, LS9 7TF, UK; n.p.west{at}


Colorectal cancer (CRC) is common with 3% of cases associated with germline mutations in the mismatch repair pathway characteristic of Lynch syndrome (LS). The UK National Institute for Health and Care Excellence recommends screening for LS in all patients newly diagnosed with CRC, irrespective of age. The Yorkshire Cancer Research Bowel Cancer Improvement Programme includes a regional LS screening service for all new diagnoses of CRC. In the first 829 cases screened, 80 cases showed deficient mismatch repair (dMMR) including four cases showing areas with loss of expression of all four mismatch repair proteins by immunohistochemistry. The cases demonstrated diffuse MLH1 loss associated with BRAF mutations and MLH1 promoter hypermethylation in keeping with sporadic dMMR, with presumed additional double hit mutations in MSH2+/−MSH6 rather than underlying LS. Recognition and accurate interpretation of this unusual phenotype is important to prevent unnecessary referrals to clinical genetics and associated patient anxiety.

  • Colorectal cancer
  • Lynch syndrome
  • deficient mismatch repair
  • MMR immunohistochemistry

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  • Handling editor Runjan Chetty.

  • Contributors NW, PQ and JA were involved in the conception and design of the work. AW, AG, GH, CY, SB, RR, LW, DW, KR, PQ and NW were involved in the acquisition, analysis and interpretation of the data. AW and NW drafted the manuscript and all other authors were involved in critically revising it. All authors gave approval for the final version submitted.

  • Funding The Yorkshire Cancer Research Bowel Cancer Improvement Programme (YCR BCIP) is funded by Yorkshire Cancer Research, Harrogate, UK.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.