1995 Deichmann Lecture--p53 tumor suppressor gene: at the crossroads of molecular carcinogenesis, molecular epidemiology and cancer risk assessment

Toxicology Letters
C C Harris

Abstract

Carcinogenesis is a multistage process involving activation of protooncogenes, e.g., ras, and inactivation of tumor suppressor genes, e.g., p53 and p16INK4.p53 is a prototype tumor suppressor gene that is well suited for analysis of mutational spectrum in human cancers; it is the most common genetic lesion in human cancers, it is a reasonable size for a molecular target, and it may indicate selection of mutations with pathobiological significance. The p53 mutational spectrum differs among cancers of the colon, lung, esophagus, breast, liver, brain, reticuloendothelial tissues and hemopoietic tissues. Analysis of these mutations can provide clues to the etiology of these diverse tumors and to the function of specific regions of p53. Transitions predominate in colon, brain and lymphoid malignancies. Mutational hotspots at CpG dinucleotides in codons 175, 245, 248, 273 and 282 may reflect endogenous mutagenic mechanisms, e.g., deamination of 5-methylcytosine to thymidine. Oxy-radicals including nitric oxide may enhance the rate of deamination. G:C to T:A transversions are the most frequent substitutions observed in cancers of the lung, breast, esophagus and liver, and are more likely to be due to bulky carcinogen-DNA adducts. G to...Continue Reading

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Citations

Apr 27, 2001·Toxicology Letters·R C SillsM L Cunningham
Apr 10, 2003·Free Radical Biology & Medicine·David A Wink, James B Mitchell
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