Malignant Complications of Chronic HCV

描述(申请人提供)：五年前，我们开始了这些病例对照研究(1R01CA85888)，以评估环境因素和慢性丙型肝炎病毒感染与埃及肝细胞癌和非霍奇金淋巴瘤(NHL)风险的相关性。我们选择埃及作为研究地点，是因为该国的丙型肝炎病毒感染率极高，肝癌和非霍奇金淋巴瘤的发病率不断上升，而且不确定丙型肝炎病毒和环境因素在这些恶性肿瘤发生中的作用和可归因性风险。研究对象包括300多例肝细胞癌患者、300例非霍奇金淋巴瘤患者和475例非肿瘤对照组。我们的结果清楚地表明，在统计学上，丙型肝炎与非霍奇金淋巴瘤和肝细胞癌有显著的相关性。接触农用杀虫剂与肝癌有关，但与非霍奇金淋巴瘤无关。此外，我们发现埃及的丙型肝炎病毒的遗传多样性比以前所知的要高得多，而且与对照组相比，基因差异更大的菌株在肝细胞癌病例中的比例过高。埃及丙型肝炎病毒的持续流行，杀虫剂与患肝癌风险的显著关联，以及缺乏相互竞争的风险因素(例如，较少的慢性乙肝病毒，中低剂量的黄曲霉毒素暴露，以及由于宗教习俗而不饮酒)，代表了一种独特的研究环境，这是其他人群无法复制的。 在这个相互竞争的续订申请中，我们提出了从原始研究结果中合乎逻辑地流动的具体目标。在接下来的5年里，我们建议继续招募新的肝细胞癌和非霍奇金淋巴瘤病例(每组300例)和非癌症对照组(N=300例与肝癌匹配，另外300例与非霍奇金淋巴瘤匹配)，因此总样本量将为600例肝细胞癌、600例非霍奇金淋巴瘤和600例对照，所有这些病例都有存储的生物样本和问卷数据。目的1评估基因-环境相互作用在肝细胞癌病因学中的作用，特别是关键抗氧化剂基因的多态在有机磷农药毒性中的作用。目的2对200对配对的肝细胞癌患者和对照的丙型肝炎病毒基因组进行测序，以确定丙型肝炎病毒基因变异的相对致癌性。目的3是在分子定义的非霍奇金淋巴瘤亚型内，检查与丙型肝炎病毒和环境因素与非霍奇金淋巴瘤的关系。这套AIMS和分子流行病学方法为研究慢性丙型肝炎的恶性并发症提供了一种新的途径。

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.