Abstract 1183: Monoallelic expression in codon 72 of <i>TP53</i> in heterozygote individuals
Authors: Ligia P. Oliveira, Bianca Cristina Garcia Lisboa, Ignacio López, Monica Marín, Dirce Maria Carraro, Renata de Almeida Coudry
Journal: Cancer Research (2012)

Abstract Background &amp; Aim: Correlations between DNA variation and human phenotypic differences, such as susceptibility to certain diseases, are not well understood. Polymorphisms can contribute to the observed variation in complex human traits, but their relative contributions remain to be determined. Expression differences between alleles of the same gene have been observed, contributing to phenotypic variation between individuals. Studies showed that variations exist in the relative allelic expression levels in certain genes of heterozygote individuals. Polymorphism at codon 72 of TP53 results in either Arginine or Proline, whose functional significance in carcinogenesis is controversial. Studies showed that the Pro72 is less efficient than Arg72 allele in suppressing cell transformation and inducing apoptosis. We have investigated if the expression of these p53 polymorphs is selectively regulated, using mRNA and DNA from colorectal cancer (CRC). Methods: 89 non-related patients treated at ACCamargo Hospital/Brazil were evaluated. DNA/RNA were isolated from frozen tumor tissue using phenol/chloroform protocol and evaluated by sequencing. Associations were analyzed by Pearson Chi-Square or Fisher Exact tests and Multiple Logistic Regression. Results: We found 24 (27%) heterozygotes tumors and 10 (41.7%) of these showed monoallelic expression: 70% (7/10) of them preferentially expressed the Pro allele. Thus, the allele frequencies showed a discrete decrease, from 0.26 for Pro allele of expression analysis to 0.25 for Pro allele of tumor genomic analysis. Previous results revealed that the p53 codon 72 expression was significantly associated with gender (P= .037), recurrence (P= .005), dirty tumor necrosis (P= .025), border pattern of tumor growth (P= .05), post chemoradiotherapy use (P= .002), p53 immunohistochemistry expression (P= .041) and TP53 mutation (P= .004), suggesting that the presence of at least one Arg72 allele is associated with better prognosis. According to multiple logistic regression the variable independently associated with the presence of the Arginine allele is the absence of tumor necrosis factor (OD= 8.64/P= .047). This is the first report describing the monoallelic expression of the p53 codon 72 in CRC and revealed that heterozygotes preferentially express the Pro allele, suggesting that the Pro allele is selectively activated during CRC development. Conclusions: The expression of the different p53 polymorphs is selectively regulated in Pro72Arg heterozygotes individuals. The silent Arg allele seems to have a negative relation with cancer susceptibility, since it is better in inducing apoptosis. The differences in the expression of heterozygotes resulted in an increase in the total numbers of Pro expressers in this cancer population. Thus, the expression status of the p53 polymorphs, rather than the genotypic status, might be a useful indicator for cancer susceptibility. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1183. doi:1538-7445.AM2012-1183