Polymorphic variants in the p53 pathway

Of all the tumor suppressor gene pathways that play a role in tumor development, few are as important as the p53 pathway. Commonly regarded as the most frequently mutated gene in human cancer, p53 is inactivated by mutation in over 50% of human tumors. Given the importance of the p53 pathway in suppressing tumor development, it is somewhat surprising to discover the existence of polymorphisms in genes in this pathway that impair its function. These include two polymorphisms in the TP53 gene itself, as well as one in the promoter of MDM2. Also evident are polymorphisms in p53 consensus elements in the promoters of target genes. The functional consequences of these polymorphisms, and their influence on cancer risk, progression, and therapy, are discussed here. Potential reasons why decreased function of this pathway might be selected for in certain populations are discussed at the end of this chapter.

The cDNA for p53 was first cloned in 1984;^{1, 2, 3} approximately 2 years later, a mobility shift in p53 protein was identified as a sequence polymorphism at amino acid 72, changing proline to arginine.^{4, 5, 6} Unfortunately, at the time of its discovery, researchers were inadvertently studying a tumor-derived mutant form of p53, with the belief that TRP53 was an oncogene. Therefore, the only functional analysis performed for these polymorphic variants was for their transforming potential, which did not differ, so the polymorphism was deemed functionally insignificant. Only in 1994, when analyzing the allele frequencies of the proline 72 and arginine 72 variants (P72 and R72, respectively) in human populations did Beckman and co-workers note statistically significant differences in allele frequency between different ethnic groups. For example, the P72 allele frequency is approximately 60% in African Americans, but only 30–35% in Caucasian Americans. Interestingly, Beckman noted that the P72 allele frequency increases in a linear manner in multiple populations as they near the equator.⁷ This led him to hypothesize that the codon 72 polymorphism might have an impact on p53 function, and that the high exposure to UV light in populations near the equator led to selection for the P72 allele.

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