McGlynn Katherine A, Hunter Kent, LeVoyer Thomas, Roush Jessica, Wise Philip, Michielli Rita A, Shen Fu-Min, Evans Alison A, London W Thomas, Buetow Kenneth H
Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH/DHHS, 6120 Executive Boulevard, Bethesda, MD 20892, USA.
Cancer Res. 2003 Aug 1;63(15):4594-601.
The genetic basis of disease susceptibility can be studied by several means, including research on animal models and epidemiological investigations in humans. The two methods are infrequently used simultaneously, but their joint use may overcome the disadvantages of either method alone. We used both approaches in an attempt to understand the genetic basis of aflatoxin B(1) (AFB(1))-related susceptibility to hepatocellular carcinoma (HCC). Ingestion of AFB(1) is a major risk factor for HCC in many areas of the world where HCC is common. Whether humans vary in their ability to detoxify the active intermediate metabolite of AFB(1), AFB(1)-exo-8,9-epoxide, is not certain but may explain why all exposed individuals do not develop HCC. To determine whether human variability in detoxification may exist, in a study of 231 HCC cases and 256 controls, we genotyped eleven loci in two families of AFB(1) detoxification genes; the glutathione S-transferases (GSTs) and the epoxide hydrolases (EPHX). After adjustment for multiple comparisons, only one polymorphism in the epoxide hydrolase family 2 locus remained significantly associated with HCC (odds ratio = 2.06, 95% confidence interval = 1.13-3.12). To determine whether additional susceptibility loci exist, we developed a mouse model system to examine AFB(1)-induced HCC. Susceptibility of 7-day-old mice from two common inbred strains (C57BL/6J, DBA/2J) was assessed. DBA/2J animals were 3-fold more sensitive to AFB(1)-induced HCC and significantly more sensitive to AFB(1) acute toxicity than were C57BL/6J animals. Analysis of the xenobiotic metabolizing genes in the two strains revealed single nucleotide polymorphisms in three genes, Gsta4, Gstt1, and Ephx1. Although the GSTT1 and EPHX1 loci did not appear to be related to HCC in the total population of the human study, a polymorphism in GSTA4 was significantly related to risk in the male subset. The mouse model also demonstrated that absent or compromised p53 was not necessary for the development of carcinogenesis. These results indicate that the comparison of results from human studies and the AFB(1)-susceptible mouse model may provide new insights into hepatocarcinogenesis.
疾病易感性的遗传基础可以通过多种方法进行研究，包括对动物模型的研究和对人类的流行病学调查。这两种方法很少同时使用，但联合使用可能会克服单独使用任何一种方法的缺点。我们同时使用这两种方法来试图了解黄曲霉毒素B1（AFB1）相关的肝细胞癌（HCC）易感性的遗传基础。在世界上许多HCC常见的地区，摄入AFB1是HCC的主要危险因素。人类对AFB1的活性中间代谢产物AFB1-exo-8,9-环氧化物的解毒能力是否存在差异尚不确定，但这可能解释了为什么并非所有暴露个体都会患上HCC。为了确定人类在解毒方面是否可能存在变异性，在一项对231例HCC病例和256例对照的研究中，我们对AFB1解毒基因的两个家族中的11个基因座进行了基因分型；谷胱甘肽S-转移酶（GSTs）和环氧化物水解酶（EPHX）。在对多重比较进行校正后，只有环氧化物水解酶家族2基因座中的一个多态性仍然与HCC显著相关（优势比=2.06，95%置信区间=1.13-3.12）。为了确定是否存在其他易感基因座，我们开发了一个小鼠模型系统来研究AFB1诱导的HCC。评估了来自两个常见近交系（C57BL/6J、DBA/2J）的7日龄小鼠的易感性。与C57BL/6J动物相比，DBA/2J动物对AFB1诱导的HCC的敏感性高3倍，对AFB1急性毒性的敏感性明显更高。对这两个品系的外源性代谢基因的分析揭示了三个基因Gsta4、Gstt1和Ephx1中的单核苷酸多态性。尽管在人类研究的总体人群中，GSTT1和EPHX1基因座似乎与HCC无关，但GSTA4中的一个多态性与男性亚组的风险显著相关。小鼠模型还表明，p53缺失或受损对于致癌作用的发生并非必要。这些结果表明，将人类研究结果与AFB1易感小鼠模型进行比较可能会为肝癌发生提供新的见解。
