MALIGNANT COMPLICATIONS OF CHRONIC HEPATITIS C VIRUS

慢性感染丙型肝炎病毒(丙型肝炎病毒)是一个主要的公共卫生问题，特别是在感染丙型肝炎病毒流行率很高的埃及。丙型肝炎的长期并发症包括肝细胞癌和非霍奇金淋巴瘤，但对非霍奇金淋巴瘤的前瞻性研究很少，因此，慢性丙型肝炎的恶性并发症的发生率在很大程度上是未知的。在评估肝细胞癌和非霍奇金淋巴瘤的丙型肝炎相关风险时，还需要考虑其他癌症风险因素的作用。这些因素包括环境暴露于致癌物和遗传的遗传易感性，需要新的研究来调查这些风险因素是否可以与丙型肝炎病毒相互作用来改变慢性感染者患恶性肿瘤的风险。此外，肿瘤抑制基因在肝细胞癌和非霍奇金淋巴瘤细胞生物学中的作用需要得到更充分的解决。为了填补这些知识空白，这项建议建立在美国和埃及科学家和研究机构正在进行的合作基础设施的基础上，以调查埃及丙型肝炎病毒相关恶性肿瘤的流行病学。我们建议进行：(1)病毒、遗传和环境危险因素之间相互关系的病例对照研究；(2)估计慢性丙型肝炎患者肝细胞癌和非霍奇金淋巴瘤发病率的前瞻性研究；(3)对肝细胞癌和非霍奇金淋巴瘤患者肿瘤组织中p53基因突变谱的研究。鉴于埃及丙型肝炎病毒和丙型肝炎病毒相关癌症的高流行率，该国环境中致癌化学物质暴露的可能性很高，以及我们已证明有能力从埃及的研究对象那里收集生物样本和获得高质量的数据，这项提议是解决有关丙型肝炎在这些类型癌症中的作用的重要问题的独特机会。

Chronic infection with hepatitis C virus (HCV) is a major public health problem, particularly in Egypt, where the prevalence of HCV infection is high. Among the long-term complications of HCV are hepatocellular carcinoma (HCC) and non-Hodgkin's lymphoma (NHL), but, particularly for NHL, few prospective studies have been done; hence, the incidence of malignant complications of chronic HCV is largely unknown. The contribution of other cancer risk factors also needs to be taken into account in assessing the HCV-associated risk of HCC and of NHL. Such factors include environmental exposures to carcinogens and inherited genetic susceptibilities, and new research is needed to investigate whether these risk factors can interact with HCV to modify the risks of malignancies in persons with chronic infections. In addition, the role of tumor suppressor genes in the biology of HCC and NHL cells needs to be addressed more fully. To fill these gaps in knowledge, this proposal builds upon an ongoing collaborative infrastructure of American and Egyptian scientists and research institutions to investigate the epidemiology of HCV- associated malignancies in Egypt. We propose to conduct: (1) a case-control study of the interrelationships among viral, genetic, and environmental risk factors for these two cancers; (2) a prospective study to estimate the incidence of HCC and NHL in persons with chronic HCV; and (3) a study of the mutational spectrum of the p53 gene in the tumor tissues of patients with HCC and NHL. Given the high prevalence of both HCV and HCV- related cancers in Egypt, the high potential for environmental exposures to carcinogenic chemicals there, and our demonstrated ability to collect biological samples and to obtain high-quality data from study subjects in Egypt, this proposal represents a unique opportunity to address important questions concerning the role of hepatitis C in these types of cancers.