Stains
MSH6

Author: Rebecca C. Obeng, M.D. (see Authors page)

Revised: 16 December 2016, last major update December 2016

Copyright: (c) 2002-2016, PathologyOutlines.com, Inc.

PubMed Search: MSH6 [title]

Cite this page: MSH6. PathologyOutlines.com website. http://www.pathologyoutlines.com/topic/stainsmsh6.html. Accessed June 22nd, 2017.
Definition / general
  • The MSH6 gene on chromosome 2 is part of the DNA mismatch repair system
  • It encodes a component of the MutS family of proteins that are involved in DNA mismatch repair, and heterodimerizes with MSH2 to form the MutS alpha complex, which serves as a bidirectional molecular switch for the mismatch repair machinery
Essential features
  • Mutations in MSH6 are associated with increased risk of colorectal cancer, hereditary nonpolyposis colon cancer, Lynch syndrome and endometrial cancer
  • MSH6 expression can be reduced by chemotherapy and radiation (Am J Surg Pathol 2010;34:1798)
Terminology
  • DNA mismatch repair protein Msh6, HNPCC5, HSAP, MutS homolog 6 (E. coli), G / T binding protein
Epidemiology
Sites
  • Ubiquitous nuclear expression in normal tissues
Pathophysiology
  • Genetic alterations in MSH6 contribute to DNA mismatch repair deficiency that leads to microsatellite instability and increased risk of cancer
  • MSH6 protein expression is unstable in absence of MSH2
  • Loss of expression of MSH2 due to mutations usually results in the loss of expression of MSH6 (Adv Anat Pathol 2009;16:405; Exp Rev Mol Diagnostics 2016;16:591)
Etiology
  • Germline or sporadic mutations in MHSH6 lead to microsatellite instability
Diagnosis
  • Screening: immunohistochemical (IHC) stain; loss of nuclear staining suggests microsatellite instability
    • Negative staining of MSH6 is usually due to mutations in MSH2 and should therefore raise suspicion for germline mutations (Cancer Treat Rev 2016;51:19)
    • Missense and point mutations that lead to nonfunctional proteins can result in false negatives on IHC
  • Confirmatory: molecular studies (PCR for microsatellite instability)
    • High (MSI-H): at least 2 of 5 unstable markers or greater than or equal to 30% of unstable markers
    • Low (MSI-L): one of five unstable markers or less than 30% of unstable markers
Prognostic factors
Case reports
Treatment
Microscopic (histologic) description
  • Normal staining pattern: nuclear
  • Cytoplasmic staining is abnormal and should not be misinterpreted as normal staining
    Microscopic (histologic) images
    Image hosted on PathOut server:
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    Colon, normal histology epithelium

    Molecular / cytogenetics description
    • National Cancer Institute recommendations: 5 microsatellite markers (BAT25, BAT26, N2S123, N5S346 and D17S250) for sequencing (Cancer Res 1998;58:5248) (additional markers may be used, however, there is no consensus on which markers to use)
    • Sanger sequencing for germline mutations
    • Multiplex ligation dependent probe amplification for large copy number variant detection
    • Next generation sequencing may also be useful