A germline substitution in the human MSH2 gene is associated with high-grade dysplasia and cancer in ulcerative colitis.
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.
Brentnall
T A
TA
Department of Medicine, University of Washington, Seattle, USA.
Rubin
C E
CE
Crispin
D A
DA
Stevens
A
A
Batchelor
R H
RH
Haggitt
R C
RC
Bronner
M P
MP
Evans
J P
JP
McCahill
L E
LE
Bilir
N
N
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