MALIGNANT COMPLICATIONS OF CHRONIC HCV

慢性丙型肝炎病毒（HCV）感染是一个主要的公共卫生问题，特别是在HCV感染流行率很高的埃及。HCV的长期并发症包括肝细胞癌（HCC）和非霍奇金淋巴瘤（NHL），但是，特别是对于NHL，很少进行前瞻性研究；因此，慢性丙型肝炎病毒的恶性并发症的发生率在很大程度上是未知的。在评估HCC和NHL的hcv相关风险时，也需要考虑其他癌症危险因素的影响。这些因素包括致癌物的环境暴露和遗传易感性，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，从而改变慢性感染者患恶性肿瘤的风险。此外，抑癌基因在HCC和NHL细胞生物学中的作用需要更充分的研究。为了填补这些知识空白，本提案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HCV相关恶性肿瘤的流行病学。我们建议进行：(1)对这两种癌症的病毒、遗传和环境风险因素之间的相互关系进行病例对照研究；(2)一项评估慢性HCV患者HCC和NHL发病率的前瞻性研究；(3) HCC和NHL患者肿瘤组织中p53基因突变谱的研究。鉴于HCV和HCV相关癌症在埃及的高患病率，致癌化学物质环境暴露的高潜力，以及我们在埃及收集生物样本和从研究对象中获得高质量数据的能力，该提案代表了一个独特的机会，可以解决有关丙型肝炎在这些类型癌症中的作用的重要问题。

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.