Genetics and Aflatoxin-Induced Hepatocellular Carcinoma

肝细胞癌是世界范围内最常见的癌症之一，约占男性新发癌症病例的7%，占女性新发癌症病例的3%。在东南亚和撒哈拉以南非洲，肝癌的发病率尤其高。在这些高发地区，被描述得最好的肝癌危险因素包括慢性感染乙肝病毒(乙肝病毒)和摄入食品中的黄曲霉毒素B1。。然而，尽管乙肝病毒携带者患肝癌的风险增加，但只有大约25%的人会发展为肝癌。此外，风险似乎在不同的地理区域有很大差异。在高发病率地区的另一个主要风险因素是霉菌毒素黄曲霉毒素B1(AFB1)，被认为是诱发DNA点突变，最著名的是P53肿瘤抑制基因249密码子的G到T颠倒。然而，接触AFB1在大多数高发病率地区非常常见，因此不能充分解释肝癌发病率的地理差异。这表明，可能还有其他风险因素，如遗传和/或环境因素，与这种风险差异有关。小鼠已被证明是一种非常有用的模式生物，可以用来揭开复杂特征的病因。大量纯合近亲交配小鼠的可获得性、高密度遗传图谱、产生转基因和靶向突变的能力使小鼠成为分析各种复杂特征的主力，包括致癌物易感性、酒精和巴比妥酸盐偏好以及自身免疫疾病。然而，由于成年小鼠对黄曲霉毒素1诱导的癌变具有明显的抵抗力，黄曲霉毒素在肝细胞癌中的作用研究相对较少。对黄曲霉毒素B_1的抗性被认为是由小鼠体内高水平的谷胱甘肽-S转移酶活性介导的，而其他模式生物和人类中没有这种活性。在乙肝病毒表面抗原阳性(HBs Ag(+))转基因小鼠中，已经证实了AFB1和乙肝表面抗原之间的协同作用，但这种相互作用的潜在遗传贡献尚未得到明确的探索。先前已经证明，虽然成年小鼠对AFB1的肝癌致癌作用具有抵抗力，但C57BLx C3HF1杂交小鼠是易感的，高达100%的动物在82周龄时患上肝癌。为了开始探索肝癌病因学中潜在的遗传变异，我们实验室扩展了这一分析，筛选了两个在肝癌发生研究中常用的近交系C57BL/6J和DBA/2J对AFB1的敏感性。我们已经证明，DBA/2J株对AFB1诱导的肝癌的敏感性是C57BL/6J株的三倍，这表明存在AFB1相关肝癌的遗传修饰物。此外，对异源代谢基因的分析表明，与AFB1相关的人类肝细胞癌相关的几个基因中存在氨基酸多态。我们目前正在进行额外的遗传分析，以确定其他潜在的修饰基因座，以及表征外源代谢基因多态的生化后果。该模型系统的进一步开发和表征有望提供对AFB1相关肝细胞癌环境和遗传成分复杂相互作用的进一步了解。

Hepatocellular carcinoma (HCC) is one of the most frequently occurring cancers worldwide, accounting for approximately 7% of the new cancer cases in men and 3% of new cancer cases in women. The incidence of HCC is particularly high in southeast Asia and sub-Saharan Africa. In these high rate areas, the best described risk factors for HCC include chronic infection with hepatitis B virus (HBV) and ingestion of aflatoxin B1 in foodstuffs. . Despite the increased risk of HCC in HBV carriers, however, only about 25% will develop HCC. In addition, the risk appears to vary significantly in different geographical regions. Another major risk factor in high rate areas, the mycotoxin aflatoxin B1 (AFB1), is thought to induce DNA point mutations, most notably the G-to-T transversion in codon 249 of the p53 tumor suppressor gene. Exposure to AFB1, however, is very common in most high rate areas and so does not adequately explain the geographic difference in HCC rates. This suggests that there may be additional risk factors, genetic and/or environmental, that are related to this disparity in risk. The mouse has proven to be a very useful model organism for unraveling the etiology of complex traits. The availability of large numbers of homozygously inbred mice, high density genetic maps, the ability to generate transgenic and targeted mutations have made the mouse a workhorse for analysis of diverse complex traits, including carcinogen susceptibility, alcohol and barbiturate preference, and auto-immune disorders. Relatively little use of the mouse has been made however for the study of role of aflatoxin in HCC due to the pronounced resistance of adult mice to AFB1-induced carcinogenesis. The resistance to AFB1 is thought to be mediated by a high glutathione-s-transferase activity in mice that is absent in other model organisms and humans. A synergism between AFB1 and the HBV surface antigen has been demonstrated in a hepatitis B virus surface antigen positive (HBsAg(+)-transgenic mouse but the underlying genetic contribution to this interaction has not been definitively explored. Previously it has been demonstrated that while adult mice are resistant to hepatocarcinogenicity of AFB1, infant C57BL x C3H F1 hybrid mice were susceptible, with up to 100% of the animals developing hepatomas by 82 weeks of age. To begin to explore the potential genetic variability in the etiology of HCC our laboratory has extended this analysis by screening the AFB1 sensistivity of two of the inbred strains commonly used in hepatocarcinogenesis research, C57BL/6J and DBA/2J. We have shown that the DBA/2J strain is three-fold more sensitive to AFB1-induced HCC than the C57BL/6J strain, demonstrating the presence of genetic modifiers for AFB1-associated HCC. In addition analysis of the xenobiotic metabolizing genes has demonstrated amino acid polymorphisms in several of the genes associated with AFB1-associated HCC in humans. We are currently performing additional genetic analysis to identify other potential modifier loci, as well as characterizing the biochemical consequences of the xenobiotic metabolizing gene polymorphisms. Further development and characterization of this model system will hopefully provide additional understanding of the complex interactions of the environmental and genetic components of AFB1-associated HCC.