MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry

Appl Immunohistochem Mol Morphol. 2012 Oct;20(5):470-7. doi: 10.1097/PAI.0b013e318249739b.


Introduction: Hereditary nonpolyposis colorectal cancer (HNPCC) is an autosomal dominant condition accounting for 2% to 4% of all colorectal cancer cases worldwide. Families with germ line mutations in 1 of 6 mismatch repair genes are known as Lynch syndrome families. The largest number of mutations has been detected in the mismatch repair genes MLH1 and MSH2, but several mutations in MSH6 have also been demonstrated.

Aim: : Whether HNPCC families are screened for mutations in mismatch repair genes often relies on their immunohistochemical profile. The aim of the present study was to evaluate this approach in Lynch families carrying mutations in MSH6.

Materials and methods: Results of the screening of the MSH6 gene in HNPCC families were compared with those obtained on immunohistochemical protein analysis.

Results: In 56 (7%) of 815 families, at least 1 MSH6 mutation, 23 definitively pathogenic mutations and 38 missense mutations or unclassified variants, and several polymorphisms in the MSH6 gene were detected. In families carrying a pathogenic MSH6 mutation, 69.6% of 23 colon adenocarcinomas showed absence of pMSH6 in tumor tissue by immunohistochemical analysis. In 34.5%, all proteins could be detected, whereas in 34.5% pMSH6 was present and pMLH1/pPMS2 was absent.

Conclusions: If genetic screening of HNPCC families depended on immunohistochemical results, a substantial number of families harboring a pathogenic mutation in MSH6 and the vast majority of families harboring an MSH6 unclassified variant would not be detected.

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics
  • Alleles
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA-Binding Proteins / genetics*
  • Exons
  • Female
  • Gene Frequency
  • Humans
  • Immunohistochemistry
  • Introns
  • Male
  • MutL Protein Homolog 1
  • MutL Proteins
  • Mutation*
  • Neoplasm Proteins / genetics
  • Nuclear Proteins / genetics
  • Polymerase Chain Reaction
  • Polymorphism, Genetic*
  • Sensitivity and Specificity
  • Sequence Analysis, DNA


  • Adaptor Proteins, Signal Transducing
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • PMS1 protein, human
  • MutL Protein Homolog 1
  • MutL Proteins