title: Hepatocellular carcinoma and polymorphisms in carcinogen-metabolizing and DNA repair enzymes in a population with aflatoxin exposure and hepatitis B virus endemicity.
abstract: High rates of hepatocellular carcinoma (HCC) in The Gambia, West Africa, are primarily due to a high prevalence of chronic hepatitis B virus infection and heavy aflatoxin exposure via groundnut consumption. We investigated genetic polymorphisms in carcinogen-metabolizing (GSTM1, GSTT1, HYL1*2) and DNA repair (XRCC1) enzymes in a hospital-based case-control study. Incident HCC cases (n = 216) were compared with frequency-matched controls (n = 408) with no clinically apparent liver disease. Although the prevalence of variant genotypes was generally low, in multivariable analysis (adjusting for demographic factors, hepatitis B virus, hepatitis C virus, and TP53 status), the GSTM1-null genotype [odds ratio (OR), 2.45; 95% confidence interval (95% CI), 1.21-4.95] and the heterozygote XRCC1-399 AG genotype (OR, 3.18; 95% CI, 1.35-7.51) were significantly associated with HCC. A weak association of the HYL1*2 polymorphism with HCC was observed but did not reach statistical significance. GSTT1 was not associated with HCC. The risk for HCC with null GSTM1 was most prominent among those with the highest groundnut consumption (OR, 4.67; 95% CI, 1.45-15.1) and was not evident among those with less than the mean groundnut intake (OR, 0.64; 95% CI, 0.20-2.02). Among participants who had all three suspected aflatoxin-related high-risk genotypes [GSTM1 null, HLY1*2 (HY/HH), and XRCC1 (AG/GG)], a significant 15-fold increased risk of HCC was observed albeit with imprecise estimates (OR, 14.7; 95% CI, 1.27-169). Our findings suggest that genetic modulation of carcinogen metabolism and DNA repair can alter susceptibility to HCC and that these effects may be modified by environmental factors.
authors.affiliation: Viral Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH/Department of Health and Human Services, Bethesda, MD 20892, USA. kirkg@mail.nih.gov
authors.forename: Gregory D
authors.initials: GD
authors.lastname: Kirk
authors.forename: Paul C
authors.initials: PC
authors.lastname: Turner
authors.forename: Yunyun
authors.initials: Y
authors.lastname: Gong
authors.forename: Olufunmilayo A
authors.initials: OA
authors.lastname: Lesi
authors.forename: Maimuna
authors.initials: M
authors.lastname: Mendy
authors.forename: James J
authors.initials: JJ
authors.lastname: Goedert
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Hall
authors.forename: Hilton
authors.initials: H
authors.lastname: Whittle
authors.forename: Pierre
authors.initials: P
authors.lastname: Hainaut
authors.forename: Ruggero
authors.initials: R
authors.lastname: Montesano
authors.forename: Christopher P
authors.initials: CP
authors.lastname: Wild
mesh_terms: D000328:Adult; D000348:Aflatoxins / Q000378:metabolism / Q000633:toxicity*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics* / Q000821:virology; D045643:DNA Repair Enzymes / Q000235:genetics* / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000235:genetics; D004781:Environmental Exposure / Q000009:adverse effects; D004851:Epoxide Hydrolases / Q000235:genetics; D005260:Female; D005714:Gambia / Q000453:epidemiology; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics; D006509:Hepatitis B / Q000150:complications; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000201:enzymology / Q000453:epidemiology* / Q000235:genetics* / Q000821:virology; D008297:Male; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012307:Risk Factors; D000076105:X-ray Repair Cross Complementing Protein 1
chemical_list: D000348:Aflatoxins; D045643:DNA Repair Enzymes; D004268:DNA-Binding Proteins; D004851:Epoxide Hydrolases; D005982:Glutathione Transferase; D000076105:X-ray Repair Cross Complementing Protein 1; C000619371:XRCC1 protein, human; C413545:glutathione S-transferase T1