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（1R01CA85888），以评估环境因素和慢性丙型肝炎病毒（HCV）感染与埃及肝细胞癌（HCC）和非霍奇金淋巴瘤（NHL）风险的关系。我们选择埃及作为研究地点，是因为该国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。超过300例HCC病例，300例NHL病例和475例非癌症对照被招募。我们的研究结果清楚地表明HCV与NHL和HCC有统计学意义的关联。暴露于农业农药与HCC有关，但与NHL无关。此外，我们发现埃及HCV的遗传多样性比以前所知的要高得多，并且与对照组相比，HCC病例中遗传差异更大的菌株过多。埃及丙型肝炎病毒的持续流行、农药与HCC风险的显著关联以及缺乏相互竞争的风险因素（例如，慢性乙型肝炎病毒很少、黄曲霉毒素暴露程度中等至较低、宗教习俗导致饮酒较少）代表了一种独特的研究环境，无法在其他人群中复制。

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.