Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis
Epidermal growth factor gene functional polymorphism and the risk of hepatocellular carcinoma in patients with cirrhosis
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DOI：
10.1001/jama.2007.65
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发表时间：
2008-01-02
影响因子：
120.7
通讯作者：
Fuchs, Bryan C.
中科院分区：
文献类型：
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作者：
Tanabe, Kenneth K.;Lemoine, Antoinette;Fuchs, Bryan C.
背景在动物模型中，表皮生长因子（EGF）在肝脏中的过度表达诱导向肝细胞癌的转化。EGF基因的多态性调节EGF levels.Objective评估人类EGF基因单核苷酸多态性、EGF表达和肝细胞癌风险之间的关系。设计、设置和参与者在人类肝细胞癌细胞系和人类肝组织中研究了61*G等位基因多态性与EGF表达的分子机制。在马萨诸塞州总医院进行了一项涉及207例肝硬化患者的病例对照研究（1999-2006），在保罗布鲁斯医院进行了一项涉及121例肝硬化患者的验证病例对照研究（1993-2006）。采用限制性内切酶片段长度多态性（RFLP）方法检测EGF基因多态性基因型。Logistic回归分析用于评估EGF基因多态性和肝细胞癌风险之间的关联。主要结果测量EGF基因多态性调节EGF水平的机制以及EGF基因多态性、EGF水平和肝细胞癌之间的关联。G/G肝癌细胞系EGF分泌量是A/A肝癌细胞系的2.3倍。G/G患者血清EGF水平是A/A患者的1.8倍，G/G患者肝脏EGF水平是A/A患者的2.4倍。在马萨诸塞州研究人群中的207例肝硬化患者中，59例同时患有肝细胞癌。等位基因频率分布分析显示，在马萨诸塞州研究人群中，G/G患者发生肝细胞癌的几率是A/A患者的4倍（比值比，4.0; 95%置信区间[0]，1.6-9.6; P= 0.002）。Logistic回归分析表明，在调整年龄、性别、种族、病因和肝硬化严重程度后，G拷贝数与肝细胞癌显著相关（G/G或A/G vs A/A;风险比，3.49; 95%CI，1.29-9.44; P= 0.01）。在法国酒精性肝硬化和肝细胞癌患者的显着关联进行了验证。结论EGF基因多态性基因型与肝硬化肝细胞癌的发展风险，通过调节EGF水平。
Context Overexpression of epidermal growth factor (EGF) in the liver induces transformation to hepatocellular carcinoma in animal models. Polymorphisms in the EGF gene modulate EGF levels.Objective To assess the relationship among human EGF gene single-nucleotide polymorphism, EGF expression, and risk of hepatocellular carcinoma.Design, Setting, and Participants Molecular mechanisms linking the 61*G allele polymorphism to EGF expression were examined in human hepatocellular carcinoma cell lines and human liver tissue. A case-control study involving 207 patients with cirrhosis was conducted at the Massachusetts General Hospital (1999-2006) and a validation case-control study involving 121 patients with cirrhosis was conducted at Hopital Paul Brousse (1993-2006). Restriction fragment-length polymorphism was used to determine the EGF gene polymorphism genotype. Logistic regression analysis was used to assess the association between the EGF polymorphism and hepatocellular carcinoma risk.Main Outcome Measures Mechanisms by which the EGF gene polymorphism modulates EGF levels and associations among EGF gene polymorphism, EGF levels, and hepatocellular carcinoma.Results Transcripts from the EGF 61*G allele exhibited more than a 2-fold longer half-life than those from the 61*A allele, and EGF secretion was 2.3-fold higher in G/G hepatocellular carcinoma cell lines than A/A cell lines. Serum EGF levels were 1.8-fold higher in G/G patients than A/A patients, and liver EGF levels were 2.4-fold higher in G/G patients than A/A patients. Among the 207 patients with cirrhosis in the Massachusetts study population, 59 also had hepatocellular carcinoma. Analysis of the distribution of allelic frequencies revealed that there was a 4-fold odds of hepatocellular carcinoma in G/G patients compared with A/A patients in the Massachusetts study population (odds ratio, 4.0; 95% confidence interval [0], 1.6-9.6; P=.002). Logistic regression analysis demonstrated that the number of copies of G was significantly associated with hepatocellular carcinoma after adjusting for age, sex, race, etiology, and severity of cirrhosis (G/G or A/G vs A/A; hazard ratio, 3.49; 95% Cl, 1.29-9.44; P=.01). The significant association was validated in the French patients with alcoholic cirrhosis and hepatocellular carcinoma.Conclusion The EGF gene polymorphism genotype is associated with risk for development of hepatocellular carcinoma in liver cirrhosis through modulation of EGF levels.