title: Germline MSH6 mutations are more prevalent in endometrial cancer patient cohorts than hereditary non polyposis colorectal cancer cohorts.
abstract: OBJECTIVE
  To determine and compare the prevalence of MSH6 (a mismatch repair gene) mutations in a cohort of families with Hereditary Non-Polyposis Colorectal Cancer (HNPCC), and in an unselected cohort of endometrial cancer patients (EC).
  
  
  METHODS
  Two patient cohorts participated in the study. A cohort of HNPCC families who were known to the Regional Medical Genetics department, and an unselected cohort of patients with a history of EC. All participants received genetic counselling on the implications of molecular testing, and blood was taken for DNA extraction with consent. All samples underwent sequencing and Multiple Ligation probe analysis (MLPA) for mutations in MSH6.
  
  
  METHODS
  DNA from one hundred and forty-three probands from HNPCC families and 125 patients with EC were included in the study.
  
  
  METHODS
  Molecular analysis of DNA in all participants from both cohorts for mutations in MSH6.
  
  
  METHODS
  Prevalence of pathogenic mutations in MSH6.
  
  
  RESULTS
  A truncating mutation in MSH6 was identified in 3.8% (95% CI 1.0-9.5%) of patients in the endometrial cancer cohort, and 2.6% (95% CI 0.5-7.4%) of patients in the HNPCC cohort. A missense mutation was identified in 2.9% and 4.4% of the same cohorts respectively. No genomic rearrangements in MSH6 were identified.
  
  
  CONCLUSIONS
  MSH6 mutations are more common in EC patients than HNPCC families. Genomic rearrangements do not contribute to a significant proportion of mutations in MSH6, but missense variants are relatively common and their pathogenicity can be uncertain. HNPCC families may be ascertained through an individual presenting with EC, and recognition of these families is important so that appropriate cancer surveillance can be put in place.
authors.affiliation: Department of Medical Genetics, Belfast City Hospital, Belfast HSC Trust, Belfast BT9 7AB, United Kingdom. lisa.devlin1@belfasttrust.hscni.net
authors.forename: Lisa A
authors.initials: LA
authors.lastname: Devlin
authors.forename: Colin A
authors.initials: CA
authors.lastname: Graham
authors.forename: John H
authors.initials: JH
authors.lastname: Price
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Morrison
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000453:epidemiology / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics; D016889:Endometrial Neoplasms / Q000453:epidemiology / Q000235:genetics*; D005260:Female; D005817:Genetic Counseling; D018095:Germ-Line Mutation; D006801:Humans; D008297:Male; D008875:Middle Aged; D009660:Northern Ireland / Q000453:epidemiology; D015995:Prevalence; D012307:Risk Factors
chemical_list: D004268:DNA-Binding Proteins; C094443:G-T mismatch-binding protein