Tumor suppressor genes: at the crossroads of molecular carcinogenesis, molecular epidemiology and human risk assessment
Introduction
The risk of human cancer can be associated with environmental, occupational, and recreational exposures to carcinogens. Cancer is a multistage process involving the inactivation of tumor suppressor genes and the activation of protooncogenes [1]. Carcinogens can affect any of these stages through genetic and epigenetic mechanisms (Fig. 1). Among the family of tumor suppressor genes, p53 holds the most prominent place in the field of cancer research. The high mutation frequency of the p53 gene in human cancer encouraged scientists to seek a better understanding of p53 [2], [3]. Since its discovery two decades ago, the diverse role of p53 in a number of vital cellular functions has surfaced and explained why mutations in this gene drive a normal cell towards cancer. p53 mutations are mostly missense type (about 75%) that can either cause a loss of tumor suppressor function or in certain cases, a gain of oncogenic function. This duality may explain the reason for the high frequency of missense p53 mutations in human cancer. Study of the p53 mutation spectra in human cancers has generated several hypotheses. One, is the association between exposure to a particular endogenous or exogenous carcinogen and the generation of a specific mutation in human cancer. Dietary exposure to AFB1 and codon 249ser mutations in hepatocellular carcinoma (HCC) is a prime example. These associations can be used for the assessment of causation using different criteria, such as the Bradford Hill criteria based on the ‘weight of the evidence principle’, which includes the strength of association and biological plausibility ([4], Table 1). Although a variety of exogenous carcinogens have been shown to selectively target p53, evidence supporting the endogenous insult of p53 is accumulating. An emerging hypothesis is the direct and indirect interactive effect of nitric oxide (NO) and p53 in carcinogenesis [5]. These and other findings point to the need of further studies on p53 for the pathogenesis, diagnosis, and treatment of human cancer.
Section snippets
Molecular archeology of tumor suppressor genes
Mutations in the evolutionarily conserved codons of the p53 tumor suppressor gene are common in diverse types of human cancer [2], [4], [6], [7] and the p53 mutational spectra differ among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues, and hemopoietic tissues. Mutational spectra of cancer-related genes, e.g. p53, BRCA-1, and p16INK4 may provide a molecular link between etiological agents and human cancer. Analysis of these mutations can provide clues
Nitric oxide, p53, and cancer
NO, an important bioregulatory and signaling molecule, may play a role in the process of carcinogenesis [5], [61], [62], [63], [64], [65]. A family of enzymes known as nitric oxide synthases (NOS) catalyze the formation of NO in the body [66], [67]. Out of the three isoforms of NOS, two are Ca2+-dependent (NOS1 and 3) and were found to be constitutively expressed, while the Ca2+-independent isoform ( iNOS or NOS2) requires induction. In recent findings, however, NOS1 and 3 also can be induced
Molecular epidemiology of human cancer risk
The association of a suspected carcinogenic exposure and cancer risk can be studied in populations with classic epidemiological techniques. However, these techniques are not applicable to the assessment of risk in individuals. A goal of molecular epidemiology is to integrate molecular biology, in vitro and in vivo laboratory models, biochemistry, and epidemiology to infer individual cancer risk [1], [103], [104], [105], [106]. Carcinogen-macromolecular adduct levels and somatic cell mutations
Acknowledgements
The editorial and graphic assistance of D. Dudek is appreciated.
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