title: A germline substitution in the human MSH2 gene is associated with high-grade dysplasia and cancer in ulcerative colitis.
abstract: OBJECTIVE
  The DNA mismatch repair gene human MSH2 shows a germline mutation in certain family members with hereditary nonpolyposis colorectal cancer. There is an increased risk of colorectal cancer in patients with ulcerative colitis (UC) with extensive disease of > 8 years' duration; however, specific constitutional predisposing genetic abnormalities have not yet been identified.
  
  
  METHODS
  A germline human MSH2 abnormality was sought in patients with UC with high-grade dysplasia or carcinoma.
  
  
  RESULTS
  After direct sequencing of exon 13 and flanking regions of human MSH2, a germline T to C substitution was shown at the -6 intronic splice acceptor site of exon 13. This substitution was found in 14 of 53 patients with UC with high-grade dysplasia or carcinoma (26%) compared with 4 of 36 high-risk patients with UC without dysplasia or cancer (11%) (P < or = 0.04) and in 7 of 80 healthy adult blood donors (9%) (P < or = 0.003). The patients with UC who had the substitution were three times more likely to develop neoplasia than patients with UC who did not carry it.
  
  
  CONCLUSIONS
  An intronic splice-site substitution in the human MSH2 gene is present in the general population but may predispose to cancer in the setting of UC.
authors.affiliation: Department of Medicine, University of Washington, Seattle, USA.
authors.forename: T A
authors.initials: TA
authors.lastname: Brentnall
authors.forename: C E
authors.initials: CE
authors.lastname: Rubin
authors.forename: D A
authors.initials: DA
authors.lastname: Crispin
authors.forename: A
authors.initials: A
authors.lastname: Stevens
authors.forename: R H
authors.initials: RH
authors.lastname: Batchelor
authors.forename: R C
authors.initials: RC
authors.lastname: Haggitt
authors.forename: M P
authors.initials: MP
authors.lastname: Bronner
authors.forename: J P
authors.initials: JP
authors.lastname: Evans
authors.forename: L E
authors.initials: LE
authors.lastname: McCahill
authors.forename: N
authors.initials: N
authors.lastname: Bilir
mesh_terms: D000328:Adult; D016009:Chi-Square Distribution; D002889:Chromosomes, Human, Pair 2; D002908:Chronic Disease; D003093:Colitis, Ulcerative / Q000150:complications / Q000235:genetics*; D003106:Colon / Q000473:pathology; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000209:etiology / Q000235:genetics*; D005260:Female; D006801:Humans; D007438:Introns; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D016017:Odds Ratio; D017354:Point Mutation; D011230:Precancerous Conditions / Q000209:etiology / Q000235:genetics*; D012307:Risk Factors