Genetic link of hepatocellular carcinoma with polymorphisms of the UDP-glucuronosyltransferase UGT1A7 gene.
OBJECTIVE
Hepatocellular carcinoma is associated with risk factors including hepatitis C, hepatitis B, cirrhosis, genetic liver diseases, and environmental carcinogens. Uridine 5'-diphosphate-glucuronosyltransferases are a superfamily of detoxifying enzymes capable of tobacco-borne carcinogen detoxification and cellular protection. This study examines the association of UGT1A7 and UGT1A9 gene polymorphisms with hepatocellular carcinoma.


METHODS
Genomic DNA from the blood of 59 patients with hepatocellular carcinoma and 70 control subjects without evidence of cancer was analyzed by UGT1A7- and UGT1A9-specific PCR, sequencing analysis, and temperature gradient gel electrophoresis.


RESULTS
Three UGT1A7 missense mutations were detected defining the UGT1A7*2, UGT1A7*3, and UGT1A7*4 alleles. Wild-type UGT1A7 alleles were present in 41.4% of controls but only in 6.8% of cancer patients (P < 0.001; odds ratio [OR], 9.73; 95% confidence interval [CI], 3.17-29.83). UGT1A7 polymorphisms were present in 93.2% of hepatocellular cancer patients, 74.5% carried the UGT1A7*3 allele (P < 0.001; OR, 10.76; 95% CI, 4.75-24.38), which combines the W208R, N129K, and R131K mutations and encodes a protein with low carcinogen detoxification activity. No UGT1A9 polymorphisms were detected.


CONCLUSIONS
The significant association of hepatocellular carcinoma with the UGT1A7*3 allele encoding a low detoxification activity protein is identified and implicates UGT1A7 as a risk gene of hepatocarcinogenesis in addition to a role as potential marker for cancer risk assessment in chronic liver disease.
Vogel
A
A
Department of Gastroenterology and Hepatology, Hannover Medical School, Hannover, Germany.
Kneip
S
S
Barut
A
A
Ehmer
U
U
Tukey
R H
RH
Manns
M P
MP
Strassburg
C P
CP
D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics*; D005091:Exons; D005260:Female; D014453:Glucuronosyltransferase / Q000235:genetics*; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic
D014453:Glucuronosyltransferase