【作者】 翟芸； 周钢桥； 邓国宏； 谢伟敏； 董晓佳； 张秀梅； 于玲； 杨灏； 苑晓燕； 张红星； 智联腾； 姚志建； 沈岩； 强伯勤； 贺福初；

【Author】 Zhai Yun Zhou Gang - Qiao Deng Guo - Hong Xie Wei - Min Dong Xiao - Jia Zhang Xiu - Mei Yu Ling Yang Hao Yuan Xiao - Yan Zhang Hong - Xing Zhi Lian - Teng Yao Zhi - Jian Shen Yan Qiang Bo - Qing He Fu - Chu Department of Genomics & Proteomics,Beijing Institute of Radiation Medicine,Beijing,China; Chinese National Human Genome Center at Beijing, Beijing, China; Department of Infectious Diseases,Southwest Hospital,Chongqing,China; Cancer Institute of Guangxi,Nanning,Guangxi,China; Beijing Proteome Research Center, Beijing, China; and Institute of Biomedical Sciences,Fudan University,Shanghai,China

【机构】 军事医学科学院放射与辐射医学研究所基因组学与蛋白质组学研究室； 重庆西南医院感染病研究所； 广西壮族自治区肿瘤医院； 国家人类基因组北方研究中心； 北京蛋白质组研究中心功能基因组学研究室；

【摘要】 目的:已在动物模型中证实雌激素受体(Estrogen Receptors,ESRs)的过表达与雌激素诱导的肝脏肿瘤密切相关;同样,人肝癌(Hepatocellular Carcinoma,HCC)的发生发展也与ESRs的过表达有着密切联系,提示ESRs在HCC的发生中发挥至关重要的作用。我们因而推测ESRs可能是肝癌的生物学候选易感基因,其遗传学变异可能会影响雌激素的功能,进而导致个体间基因型依赖的肝癌易感性的差异。雌激素主要通过结合ESR1而发挥作用。因此,我们调查ESR1的多态性是否与HCC的发生风险相关。方法:我们分别在248例HCC患者和239例正常对照个体中分型了ESR1基因的6个多态性位点:即启动子区的(TA)n重复多态性位点、外显子1第10密码子处的T29C位点、内含子1中的Pvu Ⅱ和Xba Ⅰ位点、外显子 4中第325位密码子处的C136474G以及内含子5中的A252966G位点。结果:通过非条件logistic回归分析显示,ESR1基因 5’端的3个多态性位点与HBV相关的HCC的遗传易感性有显著关联。其中,(TA)n多态性位点的H等位型的纯合子(OR =2．66,95％ CI=1．44-4．94,P=0．0018)、T29C位点的C／C基因型(OR=2．31,95％CI=1．25-4．26,P=0．0076)和 Pvu Ⅱ位点的C／C基因型(OR=2．19,95％ CI=1．27-3．78,P=0．0048)均与增加HCC的发生风险相关。而另外三个多态性位点(即Xba Ⅰ位点,C136474G和A252966G位点)与HCC的患病风险无显著的遗传学关联。分层分析未发现年龄、性别、家族史、吸烟和饮酒等常见风险因素对基因型的关联有混杂效应。以同义的T29C位点为标记,运用实时定量PCR检测显示,在杂合子细胞中T29C位点的风险等位型29C与显著增高的mRNA表达水平相关。结论:我们的研究结果提示ESR1 基因的遗传多态性在HBV相关的HCC的发生中发挥重要的作用。更多还原

【Abstract】 Objective: Overexpression of estrogen receptors (ESRs) is implicated in the development of hepatocellu- lar carcinoma (HCC) in both animal models and humans. We examined whether the ESRl polymorphisms were related to HCC risk among chronic hepatitis B virus (HBV) carriers.Methods:Six ESRl polymorphisms, which are (TA)n repeat in the promoter, T29C at codon 10 in exon 1, Pvu II and Xba I site in intron 1, C136474G at codon 325 in exon 4 and A252966G in intron 5, were genotyped in 248 HCC patients and 239 controls. The associations with the susceptibility to HCC were estimated by logistic regression. Allele - specific transcription difference of ESR1 mRNA was performed by real - time quantitative PCR. Results: We observed a statistically significantly increased susceptibility to HCC associated with the homozygous alleles with a high number of TA repeats (assigned as H/H genotype,odds ratio [OR] = 2.66,95% confidence interval [CI] = 1.44-4.94,P = 0.0018),T29C C/C genotype (OR = 2.31, 95%CI = 1.25 - 4.26, P = 0.0076)andPvu II C/Cgenotype(OR = 2.19,95%CI = 1.27 - 3.78, P = 0.0048), compared with the homozygous alleles with a low number of TA repeats (assigned as L/L genotype) ,T29C T/T and Pvu II T/T genotype, respectively. In accordance, the relative mRNA levels of the at - risk C allele of T29C were consistently higher than those of the T allele in heterozygous cells. Conclusion: Our findings suggest that the genetic polymorphism in ESRl may play a role in mediating susceptibility to HCC in Chinese HBV carriers.更多还原