乙型肝炎病毒反转录酶编码区核苷酸变异与肝癌的相关性研究

The association between mutations in the reverse transcriptase domain of hepatitis B virus polymerase gene with tumorigenesis of hepatocellular carcinoma

目的：探讨乙型肝炎病毒（hepatitisBvirus，HBy）一多聚酶（polymerase，P）基因反转录酶（reversetranscriptase，RT）区突变与肝癌发生的关系。方法：收集202例肝癌患者及202例年龄、性别匹配的慢性HBV携带者（对照组）的血清，采用病例一对照的方法进行研究；PCR法扩增HBV-P基因的RT区，对扩增产物直接测序并进行序列分析，探讨该区域基因突变与肝癌发生的关系。结果：HBIT-P基因RT区共有3个位点发生突变T895A、A904T和C955T，它们在肝癌组中的发生率均显著高于对照组，分别为47．5％坩37．1％（P=0．034）、5．4％VS1．0％（P=0．011）和5．4％vs1．5％（P=O．030）。Logistic多因素分析结果显示，T895A是肝癌的独立危险因素[比值比（oddsratio，0R）=2．230，95％可信区间（confidenceinterval，CI）：1．230～4．044，P=0．008]。A904T和C955T虽有增加肝癌风险的趋势（OR=6．523，95％CI：0．838～50．733和OR=2．904，95％C7：0．599～14．093），但差异无统计学意义。然而，A904T和C955T中有一项为阳性的发生率在肝癌组和对照组中分别是9．4％和2．5％（P=0．003），经多因素调整后统计显示，与肝癌具有相关性（OR=4．145，95％CI：1．170～14．681，P=0．028）。结论：邯V-P基因RT区存在着与肝癌发生相关的突变。

Objective： To explore the relationship between the mutations in the reverse transcriptase （RT） domain of hepatitis B virus polymerase （HBV-P） gene and the occurrence and development of hepatocellular carcinoma （HCC）. Methods： In this case-control study, the serum samples from 202 HCC patients and 202 chronic hepatitis B virus （CHB） carriers matching for age and gender were collected. The sequence of the RT domain of HBV-P gene was determined by direct sequencing following PCR amplification. The relationship between the mutations in the RT domain of HBV-P gene and the occurrence and development of HCC was analyzed. Results： The T895A, A904T and C955T mutations in the RT domain of HBV-P gene were all significantly associated with HCC compared to non-HCC controls （P = 0.034, 47.5% vs 37.1%; P = 0.011, 5.4% vs 1.0%; P = 0.030, 5.4% vs 1.5%）. Furthermore, the Logistic multivariate analysis showed that T895A was an independent risk factor for HCC [odds ratio （OR） = 2.230, 95% confidence interval （CI）： 1.230-4.044, P = 0.008]. A904T or C955T increased the risk of HCC occurrence either （OR = 6.523, 95% CI： 0.838-50.733; OR = 2.904,95% CI： 0.599-14.093）, but it did not reach statistical significance. The mutation rate of combined mutation occurrence either in A904 or C955T was 9.4% in HCC group and 2.5% in non-HCC controls （P = 0.003）. The adjusted OR was 4.145 （95% CI： 1.170-14.681）, demonstrating its significant association with HCC （P = 0.028）. Conclusion： The mutations in the RT domain ofHBV-P qene are associated with the tumorigenesis of HCC.