Genetic Predisposition to Aflatoxin-Induced Hepatocellul

肝细胞癌（HCC）是世界上最常见的癌症之一，约占男性新发癌症病例的7%和女性新发癌症病例的3%。HCC的发病率在东南亚和撒哈拉以南非洲特别高。在这些高发地区，HCC的最佳危险因素包括慢性乙型肝炎病毒（HBV）感染和食品中黄曲霉毒素B1的摄入。尽管HBV携带者发生HCC的风险增加，但只有约25%的人会发展为HCC。此外，不同地理区域的风险似乎差别很大。高发病率地区的另一个主要危险因素是霉菌毒素黄曲霉毒素B1 (AFB1)，它被认为可诱导DNA点突变，最显著的是肿瘤抑制基因p53密码子249的G-to-T翻转。然而，AFB1暴露在大多数高发病率地区非常普遍，因此不能充分解释HCC发病率的地理差异。这表明，可能还有其他风险因素，遗传和/或环境因素，与这种风险差异有关。

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.