Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin
Shen HM, Ong CN.
Department of Community, Occupational and Family Medicine, Faculty of
Medicine, National University of Singapore, Singapore
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.