MOLECULAR BIOMARKERS FOR HUMAN LIVER CANCER

人肝癌的分子生物标志物 肝细胞癌是部分地区最常见的癌症之一， 中国和撒哈拉以南非洲的肿瘤， 导致它成为癌症死亡的三大主要原因之一 全球每年至少有25万人死亡。 人类 流行病学和实验数据提供了 与黄曲霉毒素有关的关联和生物学信息 以及慢性感染B型肝炎病毒（HBV）和丙型肝炎病毒 (HCV)在这些高风险地区是这种癌症的主要风险因素。 黄曲霉毒素和HBV/HCV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、内在细胞色素P-450和 谷胱甘肽-S-转移酶激活/解毒途径 黄曲霉毒素和人的营养状况。 初级预防 通过乙肝疫苗接种和食品安全技术， 较低的黄曲霉毒素暴露量可显著降低肝癌发病率。 乙肝疫苗接种应该是一个有效的贡献者预防，如果 人们可以在感染前接种疫苗， 在亚洲和非洲。 不幸的是，疫苗还没有 用于治疗HCV。 对于黄曲霉毒素， 可以设想进行干预，但要使干预有效， 的相对作用和作用机制 黄曲霉毒素和HBV/HCV在肝癌发病机制中的作用。 我们 假设黄曲霉毒素的形成和持续水平 生物标志物反映黄曲霉毒素引起疾病的内在风险 暴露。 简而言之，该项目的目标是： 从饮食中摄入黄曲霉毒素与 其血清白蛋白加合物的形成和持久性， 尿中黄曲霉毒素代谢产物的形成和清除动力学 暴露包括DNA加合物和氧化代谢物， 如黄曲霉毒素M1、Q1、P1和巯基尿酸， HBV和/或HCV感染、营养状况和代谢多态性 status. 暴露与标记物水平之间的关系如下： 在西方两个肝癌高危人群中进行了检查 非洲及中国启东县B）确定以下方面的影响 几内亚（西非）的初级预防战略， 减少社区环境污染战略， 降低黄曲霉毒素生物标志物水平，以及c）继续跟踪- 在中国农村建立了一个前瞻性的队列来研究这种关系， 黄曲霉毒素生物标志物水平、内在危险因素和 疾病结果。

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.