Malignant Complications of Chronic HCV

描述（由申请人提供）：五年前，我们开始了这些病例对照研究（1 R 01 CA 85888），以评估环境因素和丙型肝炎病毒（HCV）慢性感染与埃及肝细胞癌（HCC）和非霍奇金淋巴瘤（NHL）风险的相关性。我们选择埃及作为研究地点，因为该国HCV的患病率极高，HCC和NHL的发病率不断增加，以及HCV和环境因素在这些恶性肿瘤发生中的作用和归因风险的不确定性。招募了超过300例HCC病例，300例NHL病例和475例非癌症对照。我们的研究结果清楚地表明，HCV与NHL和HCC的统计学显著相关。暴露于农药与HCC相关，但与NHL无关。此外，我们发现，在埃及的HCV的遗传多样性比以前已知的要高得多，并且与对照组相比，在HCC病例中，遗传差异更大的菌株比例过高。HCV在埃及的持续流行，杀虫剂与HCC风险的显著关联，以及缺乏竞争性风险因素（例如慢性HBV很少，中度至低黄曲霉毒素暴露，以及由于宗教习俗而缺乏酒精消费）代表了一种独特的研究环境，无法在其他人群中复制。 在这个竞争性的更新申请中，我们提出了从原始研究结果中逻辑地流出的具体目标。在接下来的5年时间里，我们计划继续招募HCC和NHL的新病例（每组N=300）和非癌症对照（N= 300与HCC匹配，另外300与NHL匹配），因此总样本量将为每种癌症600例HCC，600例NHL和600例对照，所有样本都有储存的生物标本和问卷数据。目的1是评估基因-环境相互作用在肝癌病因学中的作用，特别是介导有机磷农药毒性的关键抗氧化基因多态性的作用。目的二是对200对匹配的HCC病例和对照的HCV基因组进行测序，以确定HCV基因变异的相对致癌性。目的3是研究HCV和环境因素与NHL的关系，在这种异质性恶性肿瘤的分子定义亚型中。这套目标和分子流行病学方法代表了一种新的方法来研究慢性HCV感染的恶性并发症。

DESCRIPTION (provided by applicant): Five years ago we began these case-control studies (1R01CA85888) to assess the associations of environmental factors and of chronic infection with hepatitis C virus (HCV) with the risks of hepatocellular carcinoma (HCC) and non-Hodgkin's lymphoma (NHL) in Egypt. We selected Egypt as the study site because of the extremely high prevalence of HCV in that country, the increasing incidence of HCC and NHL, and uncertainty about the roles and attributable risks of HCV and environmental factors in the occurrence of these malignancies. Over 300 HCC cases, 300 NHL cases, and 475 non-cancer controls were recruited. Our results clearly demonstrate statistically significant associations of HCV with NHL and HCC. Exposure to agricultural pesticides was associated with HCC but not with NHL. In addition, we found that the genetic diversity of HCV in Egypt was much higher than previously known, and that the more genetically divergent strains were over-represented in HCC cases compared to controls. The continuing epidemic of HCV in Egypt, the significant association of pesticides with the risk of HCC, and the lack of competing risk factors (e.g. little chronic HBV, moderate to low aflatoxin exposure, and lack of alcohol consumption due to religious practices) represent a unique research setting that cannot be duplicated in other populations. In this competing renewal application we are proposing specific aims that flow logically from the original study results. During the next 5-year period we propose to continue recruiting new cases of HCC and NHL (N=300 in each group) and non-cancer controls (N=300 matched to HCC, and another 300 matched to NHL), so that the total sample size will be 600 HCC, 600 NHL, and 600 controls for each cancer, all with stored biological specimens and questionnaire data. Aim 1 is to assess gene-environment interactions in the etiology of HCC, specifically the role of polymorphisms in key antioxidant genes that mediate the toxicity of organophosphate pesticides. Aim 2 is to sequence the HCV genome from 200 matched pairs of HCC cases and controls, to determine the relative carcinogenicity of the genetic variants of HCV. Aim 3 is to examine associations with HCV and environmental factors with NHL, within molecular-defined subtypes of this heterogeneous malignancy. This set of aims and molecular epidemiology methods represents a novel approach to the study of the malignant complications of chronic HCV infection.