Genetic Predisposition to Aflatoxin-Induced Hepatocellul

黄曲霉毒素诱导的肝细胞癌的遗传倾向

• 批准号: 6755593
• 负责人: KENT William HUNTER
• 金额: --
• 依托单位: DIVISION OF CANCER EPIDEMIOLOGY AND GENETICS
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/6755593
• 关键词: aflatoxins; age difference; cancer risk; chemical carcinogen; chemical carcinogenesis; disease /disorder etiology; disease /disorder model; gene environment interaction; genetic mapping; genetic polymorphism; genetic strain; genetic susceptibility; genetically modified animals; glutathione transferase; hepatocellular carcinoma; inbreeding; laboratory mouse; model design /development; neoplasm /cancer genetics; protein structure function

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.

肝细胞癌（HCC）是全球最常见的癌症之一，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。在这些高发病率地区，最好描述的肝癌风险因素包括慢性感染B型肝炎病毒（HBV）和摄入食品中的黄曲霉毒素B1。.尽管HBV携带者患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也有很大差异。高发病率地区的另一个主要风险因素是真菌毒素黄曲霉毒素B1（AFB 1），它被认为会诱导DNA点突变，最明显的是p53肿瘤抑制基因密码子249的G-到-T颠换。然而，AFB 1暴露在大多数高发地区非常常见，因此不能充分解释HCC发病率的地理差异。这表明，可能有其他的风险因素，遗传和/或环境，与这种风险的差异。 小鼠已被证明是一种非常有用的模式生物，用于解开复杂性状的病因。大量同源近交系小鼠的可用性，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性状的主力，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AFB 1诱导的致癌作用具有明显的抵抗力，因此相对较少使用小鼠研究黄曲霉毒素在HCC中的作用。对AFB 1的抗性被认为是由小鼠中的高谷胱甘肽-S-转移酶活性介导的，而在其他模式生物和人类中不存在。在B型肝炎病毒表面抗原阳性（HBsAg（+））转基因小鼠中已经证实了AFB 1和HBV表面抗原之间的协同作用，但尚未明确探索这种相互作用的潜在遗传贡献。 先前已经证明，虽然成年小鼠对AFB 1的肝癌性具有抗性，但婴儿C57 BL x C3 H F1杂交小鼠是敏感的，到82周龄时，高达100%的动物发生肝癌。为了开始探索HCC病因学中潜在的遗传变异性，我们实验室通过筛选肝癌发生研究中常用的两种近交系C57 BL/6 J和DBA/2 J的AFB 1敏感性来扩展该分析。我们发现DBA/2 J株对AFB 1诱导的HCC的敏感性是C57 BL/6 J株的3倍，这表明AFB 1相关HCC存在遗传修饰。此外，对异生物质代谢基因的分析表明，在人类中与AFB 1相关的HCC相关的几个基因中存在氨基酸多态性。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，以及表征生物外源性代谢基因多态性的生化后果。该模型系统的进一步开发和表征将有望为AFB 1相关HCC的环境和遗传组分的复杂相互作用提供更多的理解。