title: MSH6 mutations are frequent in hereditary nonpolyposis colorectal cancer families with normal pMSH6 expression as detected by immunohistochemistry.
abstract: BACKGROUND
  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.
  
  
  OBJECTIVE
  : 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.
  
  
  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.
authors.affiliation: Department of Clinical Biochemistry, Section of Molecular Diagnostics, Aalborg University Hospital, Aalborg, Denmark. heok@rn.dk
authors.forename: Henrik
authors.initials: H
authors.lastname: Okkels
authors.forename: Karen
authors.initials: K
authors.lastname: Lindorff-Larsen
authors.forename: Ole
authors.initials: O
authors.lastname: Thorlasius-Ussing
authors.forename: Mogens
authors.initials: M
authors.lastname: Vyberg
authors.forename: Jan
authors.initials: J
authors.lastname: Lindebjerg
authors.forename: Lone
authors.initials: L
authors.lastname: Sunde
authors.forename: Inge
authors.initials: I
authors.lastname: Bernstein
authors.forename: Louise
authors.initials: L
authors.lastname: Klarskov
authors.forename: Susanne
authors.initials: S
authors.lastname: Holck
authors.forename: Henrik Bygum
authors.initials: HB
authors.lastname: Krarup
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics; D000483:Alleles; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000175:diagnosis* / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005091:Exons; D005260:Female; D005787:Gene Frequency; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns; D008297:Male; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012680:Sensitivity and Specificity; D017422:Sequence Analysis, DNA
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; C088996:PMS1 protein, human; D000070957:MutL Protein Homolog 1; D000070956:MutL Proteins