title: Germline mutations of EXO1 gene in patients with hereditary nonpolyposis colorectal cancer (HNPCC) and atypical HNPCC forms.
abstract: OBJECTIVE
  Germline mutations in one of four mismatch repair genes have been found in the majority of families with hereditary nonpolyposis colorectal cancer (HNPCC), but only in a small part of families with atypical HNPCC. The recently cloned EXO1 gene might be involved in the pathogenesis of HNPCC because the EXO1 protein strongly interacts with the MSH2 protein. To determine its role in HNPCC, EXO1 was scanned for germline mutations.
  
  
  METHODS
  All 14 exons of EXO1 were scanned for mutations in index patients from 33 families with HNPCC fulfilling the Amsterdam criteria and in 225 index patients suspected of HNPCC.
  
  
  RESULTS
  Germline variants of EXO1 were detected in 14 patients, including one splice-site mutation in a family with HNPCC and 13 missense mutations in patients with atypical HNPCC. These variants did not occur in more than 200 control individuals. From 13 of these 14 patients, tumors were available for analysis of microsatellite instability and loss of heterozygosity. Six of the tumors showed microsatellite instability. Heterozygosity analysis showed one case without EXO1 allelic loss and 12 tumors with loss of the mutant allele and retention of the normal one.
  
  
  CONCLUSIONS
  The results indicate a possible association of germline EXO1 variants with HNPCC and atypical HNPCC.
authors.affiliation: Department of Medical Genetics, University of Groningen, Groningen, The Netherlands.
authors.forename: Y
authors.initials: Y
authors.lastname: Wu
authors.forename: M J
authors.initials: MJ
authors.lastname: Berends
authors.forename: J G
authors.initials: JG
authors.lastname: Post
authors.forename: R G
authors.initials: RG
authors.lastname: Mensink
authors.forename: E
authors.initials: E
authors.lastname: Verlind
authors.forename: T
authors.initials: T
authors.lastname: Van Der Sluis
authors.forename: C
authors.initials: C
authors.lastname: Kempinga
authors.forename: R H
authors.initials: RH
authors.lastname: Sijmons
authors.forename: A G
authors.initials: AG
authors.lastname: van der Zee
authors.forename: H
authors.initials: H
authors.lastname: Hollema
authors.forename: J H
authors.initials: JH
authors.lastname: Kleibeuker
authors.forename: C H
authors.initials: CH
authors.lastname: Buys
authors.forename: R M
authors.initials: RM
authors.lastname: Hofstra
mesh_terms: D020137:Base Pair Mismatch; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000235:genetics*; D004260:DNA Repair; D045643:DNA Repair Enzymes; D005090:Exodeoxyribonucleases / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D019656:Loss of Heterozygosity; D018895:Microsatellite Repeats; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: C114331:EXO1 protein, human; D005090:Exodeoxyribonucleases; C028450:exodeoxyribonuclease I; D045643:DNA Repair Enzymes