GENETIC EPIDEMIOLOGY OF PRIMARY HEPATOCELLULAR CARCINOMA

常见癌症的风险是通过基因-基因，和/或基因- 环境的相互作用。这些相互作用对于 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（HCC）是一个独特的机会， 研究人类复杂癌症表型。流行病学研究 已经牢固确立了慢性B型肝炎病毒感染的作用 (HBV)和黄曲霉毒素B1（AFB 1）暴露作为环境危险因素。 这些暴露被很好地描述并且易于暴露 考核因此，在概念上可以审查其 与宿主遗传组成的关系在确定HCC中 易感性 在本供资期间取得了重大进展 对理解HCC复杂表型的遗传组成部分。 统计分析表明，家庭聚集与 HCC的遗传易感性。全基因组等位基因丢失 研究已经确定了多个可能含有新肿瘤的区域， 抑制基因宿主遗传结构， HBV/AFB 1暴露和HCC在病例对照研究中建立， 在群体衍生的研究人群中得到证实。 当前应用程序的目标是继续 HCC的综合遗传流行病学分析。的家族聚集性 HCC及其与HBV和AFB 1暴露的关系将在 大大增加了家庭的数量。比较基因组 将增加杂交（CGH），以允许定位推定的 肿瘤抑制基因和癌基因。据观察， 将通过遗传作图方法研究肿瘤中的频率变化， 评估它们在家庭传播中的作用。基因的作用 调节HBV感染应答的候选基因的变异性 将评估AFB 1暴露。这将通过 表达人异源物质代谢P450 cDNA及其多态性 酿酒酵母中的变异体，并确定哪些变异体 与AFB 1结合导致遗传改变。人类基因定位 将使用基于家庭的病例对照人群的方法来检验 候选黄曲霉毒素B1代谢位点多态性变异在肝癌中的作用。 促脂素缺乏和遗传变异对 将评估促脂素代谢对HCC相关终点的影响。最后， 主要易感基因、风险修饰基因座和 环境暴露及其在确定风险和家庭 将审查汇总情况。

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.