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Detection of DNA mismatch repair deficient crypts in random colonoscopic biopsies identifies Lynch syndrome patients

Familial Cancer volume 19, pages 169–175 (2020)Cite this article

Abstract

The hallmark of Lynch syndrome (LS)-associated neoplasia is DNA mismatch repair protein (MMR) deficiency. Recent studies have demonstrated that histologically normal colonic crypts in patients with LS can exhibit deficient MMR expression. The aim of this study was to determine the feasibility of detecting MMR deficient crypts in random colonoscopic biopsies of normal mucosa in patients with and without LS. Forty-nine patients, including 33 with LS, 12 without LS, and 4 with germline MMR gene variants of uncertain significance (VUS), were prospectively and blindly evaluated by immunohistochemistry for MMR deficient crypts within random normal-appearing mucosal biopsies obtained during surveillance colonoscopy. MMR deficient crypts were identified in 70% (23/33) of patients with LS and in no patients without LS (0/12) (p < 0.001). MMR deficient crypts were identified with nearly equal frequency in both LS patients with and without a cancer history and were associated with germline variants in all four MMR genes and EPCAM. MMR deficient crypts were also identified in LS patients with a history of non-colorectal cancer types, including patients with endometrial cancer, skin sebaceous neoplasms, and renal cancer. Two of the four patients with germline MMR gene VUS had MMR deficient crypts. In conclusion, MMR deficient crypts are a specific biomarker of LS and can be identified in random normal mucosal biopsies in LS patients. Evaluation for MMR deficient crypts in colonoscopic biopsies of normal mucosa can help identify LS patients.

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Affiliations

  1. Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Randall E. Brand, Beth Dudley, Eve Karloski & Rohit Das

  2. Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA

    Kimberly Fuhrer & Reetesh K. Pai

  3. Department of Laboratory Medicine and Pathology, Mayo Clinic Arizona, Scottsdale, AZ, USA

    Rish K. Pai

  4. Department of Pathology, University of Pittsburgh Medical Center, 200 Lothrop Street, Room A610, Pittsburgh, PA, 15213, USA

    Reetesh K. Pai

Authors
  1. Randall E. Brand
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  2. Beth Dudley
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  3. Eve Karloski
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  4. Rohit Das
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  5. Kimberly Fuhrer
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  6. Rish K. Pai
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  7. Reetesh K. Pai
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Correspondence to Reetesh K. Pai.

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Brand, R.E., Dudley, B., Karloski, E. et al. Detection of DNA mismatch repair deficient crypts in random colonoscopic biopsies identifies Lynch syndrome patients. Familial Cancer 19, 169–175 (2020). https://doi.org/10.1007/s10689-020-00161-w

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  • DOI: https://doi.org/10.1007/s10689-020-00161-w

Keywords

  • Lynch syndrome
  • DNA mismatch repair protein
  • MSI
  • Colorectal carcinoma
  • Colonoscopy
  • Immunohistochemistry