Mutations of the p53 tumor suppressor gene and ras oncogenes in aflatoxin

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1: Mutat Res. 1996 Oct;366(1):23-44.

Mutations of the p53 tumor suppressor gene and ras oncogenes in

aflatoxin hepatocarcinogenesis.

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.

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