Genetic link of hepatocellular carcinoma with polymorphisms of the UDP-glucuronosyltransferase UGT1A7 gene.

Abstract

BACKGROUND & AIMS:

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.

• Authors: A Vogel, S Kneip, A Barut, U Ehmer, R H Tukey, M P Manns, C P Strassburg
• Journal: Gastroenterology (Gastroenterology) Vol. 121 Issue 5 Pg. 1136-44 (Nov 2001) ISSN: 0016-5085 [Print] United States
• PMID: 11677206 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Glucuronosyltransferase

Topics

• Adolescent
• Adult
• Aged
• Aged, 80 and over
• Carcinoma, Hepatocellular (enzymology, genetics)
• Exons
• Female
• Glucuronosyltransferase (genetics)
• Humans
• Liver Neoplasms (enzymology, genetics)
• Male
• Middle Aged
• Polymerase Chain Reaction
• Polymorphism, Genetic