Lack of association between the functional polymorphisms in the estrogen-metabolizing genes and risk for hepatocellular carcinoma.
Estrogens have been proposed to act as tumor promoters and induce hepatocarcinogenesis. Recently, we observed a significant association between the risk for hepatocellular carcinoma and the polymorphisms of the estrogen receptor (ESR) alpha (ESR1) gene, supporting the hypothesis of involvement for the estrogen-ESR axis in the estrogen-induced hepatocarcinogenesis. In this study, based on another hypothesis in which estrogen metabolites can directly cause DNA damage and affect tumor initiation, we examined whether the polymorphisms of the estrogen-metabolizing enzymes (EME), which are involved in biogenesis (CYP17, CYP19), bioavailability (CYP1A1, CYP1B1), and degradation (catechol-O-methyltransferase) of the estrogens, have any bearing on the risk for hepatocellular carcinoma. Seven functional polymorphisms in five EMEs (CYP17 MspAI site, CYP19 Trp39Arg, Ile462Val and MspI site in CYP1A1, CYP1B1 Val432Leu, and Ala72Ser and Val158Met in catechol-O-methyltransferase) were genotyped in 434 patients with hepatocellular carcinoma and 480 controls by PCR-RFLP analysis. The associations between the polymorphisms and hepatocellular carcinoma risk were evaluated while controlling for confounding factors. No significant association with the risk for hepatocellular carcinoma was observed with the seven polymorphisms in hepatitis B virus carriers and non-hepatitis B virus carriers after correction for multiple comparisons. After stratification by common confounding factors of hepatocellular carcinoma, the EME polymorphism remained no significant association with the hepatocellular carcinoma risk. Furthermore, no signs of gene-gene interactions were observed for each combination of the seven polymorphisms. Our findings suggest that the polymorphisms of EMEs may not contribute significantly to the risk for hepatocellular carcinoma.
Yuan
Xiaoyan
X
The State Key Laboratory of Proteomics, Beijing Proteome Research Center, Beijing Institute of Radiation Medicine, Beijing 100850, China.
Zhou
Gangqiao
G
Zhai
Yun
Y
Xie
Weimin
W
Cui
Ying
Y
Cao
Jia
J
Zhi
Lianteng
L
Zhang
Hongxing
H
Yang
Hao
H
Zhang
Xiaoai
X
Qiu
Wei
W
Peng
Yong
Y
Zhang
Xiumei
X
Yu
Ling
L
Xia
Xia
X
He
Fuchu
F
D001141:Aromatase / Q000235:genetics; D001189:Aryl Hydrocarbon Hydroxylases / Q000235:genetics; D006528:Carcinoma, Hepatocellular / Q000201:enzymology / Q000235:genetics*; D016022:Case-Control Studies; D002394:Catechol O-Methyltransferase / Q000235:genetics; D019363:Cytochrome P-450 CYP1A1 / Q000235:genetics; D065633:Cytochrome P-450 CYP1B1; D004967:Estrogens / Q000378:metabolism*; D005260:Female; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D008113:Liver Neoplasms / Q000201:enzymology / Q000235:genetics*; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D012150:Polymorphism, Restriction Fragment Length; D012306:Risk; D013254:Steroid 17-alpha-Hydroxylase / Q000235:genetics
D004967:Estrogens; D001141:Aromatase; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D013254:Steroid 17-alpha-Hydroxylase; D002394:Catechol O-Methyltransferase