TP53Promoter Methylation in Primary Glioblastoma: Relationship withTP53mRNA and Protein Expression and Mutation Status

Abstract

Reduced expression of TP53 by promoter methylation has been reported in several neoplasms. It remains unclear whether TP53 promoter methylation is associated with reduced transcriptional and protein expression in glioblastoma (GB). The aim of our work was to study the impact of TP53 methylation and mutations on TP53 mRNA level and protein expression in 42 molecularly characterized primary GB tumors. We also evaluate the impact of all molecular alterations on the overall patient survival. The frequency of TP53 promoter methylation was found in 21.4%. To the best of our knowledge, this is the first report showing such high frequency of TP53 promoter methylation in primary GB. There was no relation between TP53 promoter methylation and TP53 mRNA level ( p = 0.5722) and between TP53 promoter methylation and TP53 protein expression ( p = 0.2045). No significant associations were found between TP53 mRNA expression and mutation of TP53 gene ( p = 0.9076). However, significant association between TP53 mutation and TP53 protein expression was found ( p = 0.0016). Our data suggest that in primary GB TP53 promoter methylation does not play a role in silencing of TP53 transcriptional and protein expression and is probably regulated by other genetic and epigenetic mechanisms associated with genes involved in the TP53 pathway.

The expression of microRNA-34a is inversely correlated with c-MET and CDK6 and has a prognostic significance in lung adenocarcinoma patients

“…p53 can induce miR-34a expression in response to DNA damage or oncogenic stress, or aberrant CpG methylation in the promoter region of the MIRN34A gene [13]. Deleted and/or mutated p53 was reported to be associated with low levels of miR-34a in chronic lymphocytic leukemia [48], although in glioblastoma, breast cancer, and NSCLC, no significant association was found between p53 mutation status and miR-34a expression [8,13,49]. Further investigation of the p53 mutation and its association with miR-34a expression are required to understand the p53-miR34a signaling pathway in human lung cancer.…”

On the Concepts and History of Glioblastoma Multiforme - Morphology, Genetics and Epigenetics

“…This type of suppression is strongly associated with sGBM. 99,100 EPIGENETIC SUPPRESSION OF EMP3 EMP3 is a suggested tumor suppressor gene with a clear oncogenic role in the nervous system. In GBM similar to other tumors, the gene is deactivated by hypermethylation of its promoter.…”

Molecular Mechanisms of p53 Deregulation in Cancer: An Overview in Multiple Myeloma

“…These results were later confirmed by Pogribny et al [70]. Since then, DNA methylation of TP53 gene or its regulatory sequences have been reported in many cancers including Ewing’s sarcoma [71], glioblastoma [72], acute lymphoblastic leukemia (ALL) [73,74], human hepatocellular carcinoma [75], ovarian cancer [76], breast cancer [77] and also in MM [78,79]. On the contrary, lack of DNA methylation of TP53 has also been found in other diseases like cutaneous squamous cell carcinomas [80], sporadic adrenocortical cancers [81] and myelodysplastic syndromes (MDS) [82].…”

“…On the contrary, in rectal cancer, methylation of p53 (investigated by methylation sensitive digestion) was correlated with apoptosis but not with p53 protein level [84]. Lack of correlation between p53 DNA methylation and protein level was also observed in glioblastoma multiforme [72]. …”