Malignant Complications of Chronic HCV

慢性丙型肝炎的恶性并发症

• 批准号: 7236645
• 负责人: Christopher A Loffredo
• 金额: $ 30.78万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-29 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7236645
• 关键词: Aflatoxins; Agriculture; Alcohol abuse; Alcohol consumption; American; Antioxidants; Area; Biological; Biological Assay; COMT gene; Cancer Control; Case-Control Studies; Catechol O-Methyltransferase; Chronic; Country; Custom; Data; Desert Climate; Egypt; Environment; Environmental Exposure; Environmental Risk Factor; Epidemic; Epidemiologic Methods; Etiology; Exposure to; Functional disorder; GSTT1 gene; GSTT1 protein; Genes; Genetic; Genetic Polymorphism; Genetic Predisposition to Disease; Genetic Variation; Genome; Genotype; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Heterogeneity; High Prevalence; Incidence; Infection; Knowledge; Lymphoma; Malignant - descriptor; Malignant Neoplasms; Mediating; Molecular; NAD(P)H dehydrogenase (quinone) 1, human; NQO1 gene; Non-Hodgkin' s Lymphoma; Numbers; Organophosphates; Oxidative Stress; Pathology; Pattern; Pesticides; Phenotype; Population; Positioning Attribute; Primary carcinoma of the liver cells; Principal Investigator; Questionnaires; Recruitment Activity; Relative (related person); Religion and Spirituality; Research; Research Design; Risk; Risk Factors; Role; SOD2 gene; Sample Size; Science; Scientist; Site; Specimen; Statistically Significant; Testing; Tobacco smoke; Toxic effect; Uncertainty; Variant; Viral; Viral Genome; Virus; Work; biological adaptation to stress; carcinogenicity; case control; catalase; cell injury; gene environment interaction; genetic risk factor; genetic variant; novel; novel strategies; programs; tumor

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.

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感染与丙型肝炎病毒（HCV）与肝细胞癌（HCC）和非霍迪格金淋巴瘤（HCV）的风险。我们之所以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，以及有关HCV的角色和可归因于这些恶性肿瘤发生的角色和可归因的风险的不确定性。招募了超过300例HCC病例，300例NHL病例和475例非癌症对照。我们的结果清楚地表明，HCV与NHL和HCC具有统计学意义的关联。接触农业农药与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已知的要高得多，并且与对照组相比，在HCC病例中，遗传上不同的菌株在HCC病例中占代表性过高。 HCV在埃及的持续流行，农药与HCC风险的显着关联以及缺乏竞争风险因素（例如，慢性HBV很少，中度至低的黄曲毒素暴露以及由于宗教习惯而缺乏饮酒剂）代表了在其他人群中无法重复的独特研究环境。 在此竞争性更新应用中，我们提出了从原始研究结果逻辑上流动的特定目标。在接下来的5年期间，我们建议继续招募HCC和NHL的新病例（每组n = 300）和非癌症对照（n = 300匹配与HCC匹配，另外300匹与NHL匹配），以便总样本量为600 HCC，600 NHL，600 NHL，以及每个癌症的600个癌症控制，均具有存储的生物学数据。目的1是评估HCC病因中的基因环境相互作用，特别是多态性在介导有机磷酸盐农药毒性的关键抗氧化基因中的作用。 AIM 2是从200对HCC病例和对照对中序列的HCV基因组，以确定HCV遗传变异的相对致癌性。 AIM 3是在这种异质性恶性肿瘤的分子定义亚型内检查与HCV和与NHL的环境因素的关联。这组目标和分子流行病学方法代表了一种研究慢性HCV感染的恶性并发症的新方法。