Shen H M, Ong C N
Department of Community, Occupational and Family Medicine, Faculty of Medicine, National University of Singapore, Singapore.
Mutat Res. 1996 Oct;366(1):23-44. doi: 10.1016/s0165-1110(96)90005-6.
Aflatoxin B1 (AFB1) is classified as a group I carcinogen in humans by IARC. However, the exact mechanisms of AFB1 hepatocarcinogenesis have not been fully elucidated. Recent studies have suggested that oncogenes are critical molecular targets for AFB1, and AFB1 causes characteristic genetic changes in the p53 tumor suppressor gene and ras protooncogenes. Up to date, more than 1500 human hepatocellular carcinoma (HCC) samples have been examined for p53 mutations with respect to different AFB1 exposure levels. The most significant finding is that more than 50% of HCC patients from high aflatoxin exposure areas such as southern Africa and Qidong, China harboured a codon 249 G to T transversion in the p53 tumor suppressor gene, which is found to be consistent with the mutagenic specificity of AFB1 observed in vitro. In contrast, this mutational pattern is not found in HCC samples from moderate or low aflatoxin exposure countries or regions. Therefore, this hot-spot mutation is believed to be a molecular fingerprint linking the initial event of AFB1-DNA adduct formation with the ultimate development and progress of human HCC. However, some important points still remain to be explicated. First, in many of these studies, the systematic evaluation of AFB1 exposure is rather limited and the classification of AFB1 exposure level is speculative and confusing, without the definite evidence for the actual aflatoxin exposure level. Second, the role of hepadnaviral infection has to be considered in the induction of this unique mutational spectrum. On the other hand, ras oncogene mutations are frequently found in AFB1-induced HCC samples in experimental animals, while the frequency of ras mutation in human HCC in contrast is much lower than that of p53. Recent studies have provided additional evidence that reactive oxygen species (ROS) and oxidative DNA damage may be involved in AFB1-induced p53 and ras mutations. In future, follow-up cohorts exposed to different levels of AFB1 combined with the determination of putative gene markers are much needed.
黄曲霉毒素B1（AFB1）被国际癌症研究机构（IARC）列为对人类的I类致癌物。然而，AFB1致肝癌的确切机制尚未完全阐明。最近的研究表明，癌基因是AFB1的关键分子靶点，AFB1会导致p53肿瘤抑制基因和ras原癌基因发生特征性的基因变化。到目前为止，已经针对不同的AFB1暴露水平，对1500多份人类肝细胞癌（HCC）样本进行了p53突变检测。最显著的发现是，来自高黄曲霉毒素暴露地区（如非洲南部和中国启东）的HCC患者中，超过50%在p53肿瘤抑制基因中存在密码子249由G到T的颠换，这一发现与体外观察到的AFB1的诱变特异性一致。相比之下，在黄曲霉毒素暴露水平中等或较低的国家或地区的HCC样本中未发现这种突变模式。因此，这种热点突变被认为是将AFB1-DNA加合物形成的初始事件与人类HCC的最终发展和进展联系起来的分子指纹。然而，一些重要问题仍有待阐明。首先，在许多这些研究中，对AFB1暴露的系统评估相当有限，AFB1暴露水平的分类具有推测性且令人困惑，缺乏实际黄曲霉毒素暴露水平的确切证据。其次，在诱导这种独特的突变谱时必须考虑乙肝病毒感染的作用。另一方面，在实验动物中，ras癌基因突变在AFB1诱导的HCC样本中经常出现，而在人类HCC中ras突变的频率相比之下远低于p53。最近的研究提供了更多证据表明活性氧（ROS）和氧化性DNA损伤可能参与AFB1诱导的p53和ras突变。未来，非常需要对暴露于不同水平AFB1的后续队列进行研究，并结合对假定基因标志物的检测。
