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首页> 外文期刊>Hepatology: Official Journal of the American Association for the Study of Liver Diseases >Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma.
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Genetic variations at loci involved in the immune response are risk factors for hepatocellular carcinoma.

机译：参与免疫应答的基因座的遗传变异是肝细胞癌的危险因素。

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摘要

Primary liver cancer is the third most common cause of cancer-related death worldwide, with a rising incidence in Western countries. Little is known about the genetic etiology of this disease. To identify genetic factors associated with hepatocellular carcinoma (HCC) and liver cirrhosis (LC), we conducted a comprehensive, genome-wide variation analysis in a population of unrelated Asian individuals. Copy number variation (CNV) and single nucleotide polymorphisms (SNPs) were assayed in peripheral blood with the high-density Affymetrix SNP6.0 microarray platform. We used a two-stage discovery and replication design to control for overfitting and to validate observed results. We identified a strong association with CNV at the T-cell receptor gamma and alpha loci (P < 1 x 10(-15)) in HCC cases when contrasted with controls. This variation appears to be somatic in origin, reflecting differences between T-cell receptor processing in lymphocytes from individuals with liver disease and healthy individuals that is not attributable to chronic hepatitis virus infection. Analysis of constitutional variation identified three susceptibility loci including the class II MHC complex, whose protein products present antigen to T-cell receptors and mediate immune surveillance. Statistical analysis of biologic networks identified variation in the "antigen presentation and processing" pathway as being highly significantly associated with HCC (P = 1 x 10(-11)). SNP analysis identified two variants whose allele frequencies differ significantly between HCC and LC. One of these (P = 1.74 x 10(-12)) lies in the PTEN homolog TPTE2. Conclusion: Combined analysis of CNV, individual SNPs, and pathways suggest that HCC susceptibility is mediated by germline factors affecting the immune response and differences in T-cell receptor processing.
机译：原发性肝癌是全世界与癌症相关的死亡的第三大最常见原因，西方国家的发病率正在上升。对这种疾病的遗传病因知之甚少。为了确定与肝细胞癌（HCC）和肝硬化（LC）相关的遗传因素，我们对亚洲无关人群进行了全面的全基因组变异分析。使用高密度Affymetrix SNP6.0微阵列平台在外周血中检测拷贝数变异（CNV）和单核苷酸多态性（SNP）。我们使用了一个两阶段的发现和复制设计来控制过度拟合并验证观察到的结果。与对照组相比，我们在HCC病例中发现了CNV在T细胞受体gamma和alpha位点（P <1 x 10（-15））上的强烈关联。这种变化似乎起源于体细胞，反映出肝病患者和健康个体的淋巴细胞中T细胞受体加工之间的差异，这并不归因于慢性肝炎病毒感染。体质变异的分析确定了三个易感基因座，包括II类MHC复合体，其蛋白产物为T细胞受体提供抗原并介导免疫监视。生物网络的统计分析确定“抗原呈递和加工”途径中的变异与肝癌高度相关（P = 1 x 10（-11））。 SNP分析确定了两个变异，其等位基因频率在HCC和LC之间显着不同。其中之一（P = 1.74 x 10（-12））位于PTEN同源物TPTE2中。结论：对CNV，单个SNP和途径的综合分析表明，HCC易感性是由影响免疫应答和T细胞受体加工差异的种系因素介导的。

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