HCV genetic variation and hepatocellular carcinoma

描述（由申请人提供）：慢性丙型肝炎病毒（HCV）感染可引起肝炎和肝细胞癌（HCC）。HCV诱导的致癌机制可能包括病毒蛋白的直接致癌刺激和炎症的间接致瘤作用。可诱导直接致癌刺激的病毒基因包括核心、NS 3和NS 5A，并且炎症可由NS 3和NS 5A调节。HCV的遗传变异可能会明显影响其致癌潜力，但对于HCV的高度多样性如何影响肿瘤发生尚无共识，因为病毒遗传分析仅限于对基因组小区域的详细检查或在基因型的不敏感水平上表征HCV的多样性。此外，生化分析归因于致癌潜力的HCV蛋白产生了相互矛盾的结果，可能是因为很少有解决HCV的遗传多样性。因此，我们将采用协调遗传和生化方法，对HCV的遗传变异对致癌潜力的影响进行全面分析。假设：HCV基因变异通过调节促进肿瘤生长和/或中度炎症的病毒蛋白的功能而促进HCC的发展。目标1。HCV序列变异与HCC发生的相关性我们将对20例发生HCC的患者和20例无HCC的随机对照人群的完整HCV蛋白编码区进行测序，并评估与HCC相关的序列模式的存在。目标二。确定遗传变异如何影响HCV蛋白的促肿瘤活性。我们将表达变异核心，NS 3/4A和NS 5A基因从肝癌和对照组在目标1和测量他们的能力，转化细胞和改变转录的细胞周期调控基因。我们还将评估在目标1中观察到的与HCC遗传相关的其他HCV基因。目标3：确定遗传变异如何影响HCV蛋白减轻炎症的能力。我们将在目标1中表达来自HCC和对照受试者的变体NS 3/4A和NS 5A基因，并测量它们对抗炎症反应的活性。我们还将评估其他HCV基因，在目标1中观察到与HCC的新遗传相关性。这些数据将阐明HCV促进癌症的机制，因此可以确定延迟或停止HCC发展的方法。它们还可能通过发现与HCC相关的病毒基序，提高识别HCC发展风险最高的患者的能力。

DESCRIPTION (provided by applicant): Chronic Hepatitis C virus (HCV) infection causes hepatitis and hepatocellular carcinoma (HCC). The mechanisms of HCV-induced carcinogenesis are likely to include direct oncogenic stimuli by viral proteins and indirect tumorigenic effects from inflammation. Viral genes that may induce direct oncogenic stimuli include core, NS3, and NS5A, and inflammation could be modulated by NS3 and NS5A. HCV's genetic variation could clearly affect its oncogenic potential, but there is no consensus on how HCV's high diversity may affect oncogenesis because viral genetic analyses have been limited to detailed inspection of small regions of the genome or to characterizing HCV's diversity at the insensitive level of the genotype. Furthermore, biochemical analyses attributing oncogenic potential to HCV proteins have yielded conflicting results, possibly because few have addressed HCV's genetic diversity. Therefore, we will perform a comprehensive analysis of the effect of HCV's genetic variation on carcinogenic potential employing coordinated genetic and biochemical approaches. Hypothesis: HCV genetic variation contributes to development of HCC by modulating function of viral proteins that promote tumor growth and/or moderate inflammation. Aim 1. Correlate HCV sequence variation with development of HCC. We will sequence the complete HCV protein coding region from 20 patients who developed HCC and from 20 random population controls without HCC and the presence of sequence patterns that correlate with HCC will be evaluated. Aim 2. Determine how genetic variation affects putative tumor promoting activities of HCV proteins. We will express variant core, NS3/4A, and NS5A genes from HCC and control subjects in Aim 1 and measure their ability to transform cells and to alter transcription of cell-cycle regulatory genes. We will also assess other HCV genes for which genetic correlations with HCC are observed in Aim 1. Aim 3. Determine how genetic variation affects the ability of HCV proteins to moderate inflammation. We will express variant NS3/4A and NS5A genes from HCC and control subjects in Aim 1 and measure their activities proposed to counteract inflammatory responses. We will also assess other HCV genes for which novel genetic correlations with HCC are observed in Aim 1. These data will clarify the mechanism(s) by which HCV promotes cancer, and hence may identify approaches to delay or halt development of HCC. They may also lead to greater ability to identify patients at highest risk for development of HCC through discovery of viral motifs associated with HCC.