GENETIC EPIDEMIOLOGY OF PRIMARY HEPATOCELLULAR CARCINOMA

常见癌症的风险是通过基因-基因和/或基因-基因产生的。 环境相互作用。人们对这些相互作用知之甚少 大多数癌症的部分原因是暴露的多样性和复杂性。 原发性肝细胞癌是一种独特的治疗机会 研究人类的一种复杂的癌症表型。流行病学研究 已经牢固确立了慢性乙肝病毒感染的作用 (乙肝病毒)和黄曲霉毒素B1(黄曲霉毒素B1)暴露为环境风险因素。 这些暴露是描述得很好的，并且容易受到暴露 评估。因此，从概念上讲，可以检查它们的 确定肝细胞癌与宿主遗传构成的关系 敏感度。 在本供资期间取得了重大进展。 有助于了解肝细胞癌复杂表型的遗传成分。 统计分析表明，家庭聚集性与 肝癌的遗传易感性。全面的全基因组等位基因丢失 研究已经确定了可能含有新肿瘤的多个区域 抑制基因。寄主遗传构成、 乙肝病毒/黄曲霉毒素B受体1暴露与肝细胞癌建立在c病例对照研究和 在队列衍生的研究人群中得到证实。 当前应用程序的的目标是继续 肝癌的综合遗传流行病学分析。家族聚集性 肝癌及其与乙肝病毒和黄曲霉毒素B受体1暴露的关系将在 大大扩大了家庭的收集范围。比较基因组 将添加杂交(CGH)以允许假定的本地化 肿瘤抑制基因和癌基因。观察到的地区有高 将通过基因图谱方法研究肿瘤的频率变化，以 评估它们在家族传播中的作用。基因的作用 调节对乙肝病毒感染反应的候选基因的变异性 并将评估AFB1的暴露情况。这将通过以下方式实现 异源代谢人P450基因的表达及其多态 酿酒酵母的变异体及其在酿酒酵母中的鉴定 与AFB1结合会导致基因改变。人类基因图谱 使用基于家庭的病例对照人群的方法将被用于测试 候选AFB1代谢位点的多态变异在肝细胞癌中的作用 促脂蛋白缺乏和遗传变异性对高脂血症的影响 对肝细胞癌相关终点的趋脂性代谢进行评估。最后， 主要易感基因、风险修饰基因和 环境暴露及其在确定风险和家族性方面的作用 我们将检查聚合情况。

The risk of common cancer is produced through gene-gene, and/or gene- environment interactions. These interactions are poorly understood for most cancers in part due to the diversity and complexity of the exposures. Primary hepatocellular carcinoma (HCC) represents a unique opportunity to investigate a complex cancer phenotype in humans. Epidemiologic studies have firmly established the role of chronic hepatitis B virus infection (HBV) and aflatoxin B1 (AFB1) exposure as environmental risk factors. These exposures are well described and are amenable to exposure assessment. it is therefore conceptually possible to examine their relationship to host genetic constitution in determining HCC susceptibility. Significant progress has been made during the current funding period toward understanding the genetic components of the HCC complex phenotype. Statistical analyses has demonstrated familial aggregation consistent with genetic susceptibility of HCC. Comprehensive genome-wide allele loss studies have identified multiple regions which could contain novel tumor suppressor genes. An interaction between host genetic constitution, HBV/AFB1 exposures, and HCC was established in c case-control study and confirmed in a cohort-derived study population. It is the goal of the of the current application to continue the integrated genetic epidemiologic analysis of HCC. Familial aggregation of HCC and its relationship to HBV and AFB1 exposure will be examined in a significantly expanded collection of families. Comparative genome hybridization (CGH) will be added to permit the localization of putative tumor suppressor genes and oncogenes. Regions observed to have high frequency changes in tumors will be studied by genetic mapping methods to assess their role in familial transmission. The role of genetic variability in candidate genes that modulate responses to HBV infection and AFB1 exposure will be assessed. This will be accomplished by expressing human xenobiotic metabolizing P450 cDNAs and their polymorphic variants in Saccharomyces cerevisiae and determining which ones in combination with AFB1 cause genetic alterations. Human gene mapping methods using a family-based case-control population will be used to test the role polymorphic variants of candidate AFB1 metabolizing loci in HCC. The influence of lipotrope insufficiency and genetic variability in lipotrope metabolism to HCC related end-points will be assessed. Finally, the interaction of major susceptibility genes, risk modifying loci, and environmental exposures and their role in determining risk and familial aggregation will be examined.