A germline substitution in the human MSH2 gene is associated with high-grade dysplasia and cancer in ulcerative colitis

Gastroenterology. 1995 Jul;109(1):151-5. doi: 10.1016/0016-5085(95)90280-5.


Background & aims: 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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Adult
  • Chi-Square Distribution
  • Chromosomes, Human, Pair 2
  • Chronic Disease
  • Colitis, Ulcerative / complications
  • Colitis, Ulcerative / genetics*
  • Colon / pathology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / etiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Female
  • Humans
  • Introns
  • Logistic Models
  • Male
  • Middle Aged
  • Odds Ratio
  • Point Mutation*
  • Precancerous Conditions / etiology
  • Precancerous Conditions / genetics*
  • Risk Factors