Abstract 783: Mutational status of the p53 tumor suppressor gene is associated with expression of GSTP1 allelic variants in human GBM..

Abstract

Abstract The tumor suppressor and transcription factor, p53, regulates the transcription of a large number of genes that control key cellular functional, such as, cell cycle arrest, DNA repair, senescence and apoptosis, and its mutational inactivation of p53 has been implicated in tumor development and progression. Mutation in p53 is a common genetic abnormality in GBM and other cancers and several studies have associated wild type p53 with high tumor drug resistance. Our laboratory previously reported that the polymorphic human GSTP1 gene is a transcriptional target of and is activated by p53 via a canonical p53 binding motif located in intron 4 of the GSTP1 gene. The ability of the p53 wild type to transcriptionally activate the GSTP1 gene, thus, defines a novel mechanism of protecting the genome and enhancement tumor drug resistance. The ability of the different GSTP1 alleles to protect against the toxicity of anticancer agents plays an important factor in this GSTP1-mediated tumor drug resistance. In a previous study, we showed that p53 mutations in GBM spanned the entire p53 gene, with the majority of the mutations in the DNA binding domain and that GSTP1 expression correlated, in most cases with wild type p53. In the present study, we examined the relationship between p53-dependent GSTP1 gene activation genetic polymorphism and expression in human GBM. We sequenced the p53 gene in 52 primary human GBMs, genotyped these tumors for their GSTP1 allelic status and determined the expression of the GSTP1 gene transcripts by quantitative PCR. The results showed the GSTP1*A allele to most highly (40%) expressed in the tumors and of these 27% harbored wild-type p53. In contrast, GSTP1*C allele was not only the least prevalent allele but also had the least association with wild-type p53. GSTP1*B, as well as, heterozygous GSTP1 alleles were intermediate in their association with p53 mutational status of the tumors. The level of expression of the individual genes also correlated with the presence of wild-type p53 in inversely with mutant p53. These results demonstrate a significant impact of p53 mutational status, not only in mediating the level of GSTP1 gene expression but also that it is related to the specific allelic form of GSTP1 that is expressed. This suggest that p53 mutational status and both GSTP1 expression and allele polymorphism may interact together to mediate glioma drug resistance. Citation Format: Gamil R. Antoun, Francis Ali-Osman. Mutational status of the p53 tumor suppressor gene is associated with expression of GSTP1 allelic variants in human GBM. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 783. doi:10.1158/1538-7445.AM2013-783