MOLECULAR BIOMARKERS FOR HUMAN LIVER CANCER

人肝癌的分子生物学标记物 肝细胞癌是部分地区最常见的癌症之一。 中国与撒哈拉以南非洲的关系以及该肿瘤的不良预后 结果它成为导致癌症死亡的三大原因之一 全世界每年至少有25万人死亡。人类 流行病学和实验数据提供了统计数据 与黄曲霉毒素有关的关联性和生物学信息 以及慢性感染乙肝病毒和丙型肝炎病毒 (丙型肝炎病毒)是这些高危地区这种癌症的主要危险因素。 黄曲霉毒素和乙肝病毒/丙型肝炎病毒在病因中的作用程度 这种疾病的发病率可能受到多种因素的影响，包括 致癌物暴露水平、内源性细胞色素P-450和 谷胱甘肽-S-转移酶激活/解毒途径 黄曲霉毒素，以及人的营养状况。一级预防 通过接种乙肝疫苗和食品安全技术来应对 较低的黄曲霉毒素暴露可以显著降低肝癌发病率。 在以下情况下，接种乙肝疫苗应是预防的有效因素 人们可以在感染前接种疫苗，这通常会发生 在亚洲和非洲两岁之前。不幸的是，疫苗尚未问世。 为丙型肝炎病毒而开发。对于黄曲霉毒素来说，类似的靶标 干预是可以设想的，但要想奏效，需要 的相对作用和作用机制的确定 黄曲霉毒素和乙肝病毒/丙型肝炎病毒在肝癌发病机制中的作用我们的 假说是黄曲霉毒素的形成和持久性水平 生物标志物反映黄曲霉毒素致病的内在风险 曝光。简而言之，本项目的目标是：a)界定 膳食中黄毒素暴露与黄毒素之间的精确时间关系 其血清白蛋白加合物的形成和存留 黄曲霉毒素尿代谢物的形成和清除动力学 暴露包括DNA加合物和氧化代谢产物 作为黄曲霉毒素M1、Q1、P1和经调节的硫代尿酸 乙肝病毒和/或丙型肝炎病毒感染、营养和代谢多态 状态。暴露和标记水平之间的关系将是 在西方两个肝癌高危人群中进行检查 非洲和启东县，中华人民共和国b)，以确定 几内亚(西非)使用有针对性的初级预防战略 社区环境中的减少污染战略 降低黄曲霉毒素生物标志物水平，以及c)继续跟进- 在农村建立前瞻性队列，检查中国与农村的关系 黄曲霉毒素生物标志物水平、内在危险因素与 疾病结局。

Molecular Biomarkers for Human Liver Cancer Hepatocellular carcinoma is one of the most common cancers in parts of China and sub-Saharan Africa and the poor prognosis of this tumor results in it being one of the three leading causes of cancer deaths world-wide with at least 250,000 deaths per year. Human epidemiology and experimental data have provided the statistical association and biological information necessary to implicate aflatoxins and chronic infection with hepatitis B virus (HBV) and hepatitis C virus (HCV) as major risk factors for this cancer in these high-risk areas. The degree that aflatoxins and HBV/HCV contribute to the causation of this disease may be affected by a number of factors including; the level of carcinogen exposure, intrinsic cytochrome P-450 and glutathione-S-transferase activation/detoxification pathways for aflatoxins, and the nutritional status of the person. Primary prevention measures by vaccination against HBV and food safety techniques to lower aflatoxin exposure could significantly lower liver cancer rates. HBV vacccination should be an effective contributor to prevention if people can be inoculated prior to infection, which generaly occurs before age two in Asia and Africa. Unfortunately, a vaccine has yet to be developed for HCV. For aflatoxins a similar targeted intervention could be envisaged, but for this to be effective requires determination of the relative roles and mechanisms of action of aflatoxin and HBV/HCV in the etiopathogenesis of liver cancer. Our hypothesis is that levels of formation and persistence of aflatoxin biomarkers reflect intrinsic risk of disease development from aflatoxin exposures. Briefly, the aims of this project are: a) To define the precise temporal relationships between dietary exposure to afltoxins and the formation and persistence of its serum albumin adducts and the kinetics of formation and removal of urinary metabolites of aflatoxin exposures including the DNA adducts and oxidative metabolites such as aflatoxin M1, Q1, P1 and the mercapturic acids as modulated by HBV and/or HCV infection, nutriture and metabolic polymorphism status. The relation between exposure and marker levels will be examined in two populations at high risk for liver cancer in West Africa and Qidong County, P.R.C. b) To determine the impact of primary prevention strategies in Guinea (West Africa) using a targeted contamination reduction strategy in community settings towards the reduction of aflatoxin biomarkers levels, and c) To continue to follow- up a prospective cohort in rural China to examine the relation and interaction between aflatoxin biomarker levels, intrinsic risk factors and disease outcome.