Assessment of p53 mutations, expression and prognosis in bladder cancer patients from Jordan: Identification of novel deletion mutations in the DNA-binding domain

Bladder cancer is the most common cancer of the urinary tract with an estimate of 401,000 new cases diagnosed annually worldwide. In Jordan, bladder cancer accounts for 4.3% of all newly diagnosed cancer cases. Several studies have linked p53 molecular changes to tumor initiation, invasion, metastasis, and chemoresistance. In the present study, we investigated a cohort of 121 bladder cancer patients with various grades and stages of the tumor for molecular changes in p53. Overexpression of p53 was shown in 22%, 46%, 71% and 25% pTa, pT1, pT2 and pT4 cases, respectively. Additionally, p53 was overexpressed in 19%, 38% and 74% of G1, G2 and G3 cases of bladder cancer, respectively. p53 expression is not significantly associated with the stage or grade of the disease. Mutational analysis of exons 4-8 of p53 identified the following previously reported point mutations R72P (58%), P67T (9%), A159P (0.7%), D185N (28%), G199 V (0.7%), G199E (0.7%), D208N (0.7%), R283P (1.4%). Furthermore, we were able to identify two new deletion mutations located in the DNA-binding domain in two patients. The first mutation was a result of one nucleotide deletion in exon 5 causing a frameshift at codon 115 resulting in a truncated 168 amino acids long p53 protein and the second is a result of a whole codon deletion in exon 6 resulting in a p53 protein missing a valine residue at codon 218. P53 mutations were found to be significantly associated with late stage (pT2-pT4) muscle-invasive bladder tumors. Survival analysis indicates significant differences of overall survival between the patients with the p53 overexpression and those with negative p53 staining (p = 0.0041). Additionally, were able to observe a significant difference of overall survival between p53 mutants and p53 wild-type (p = 0.0062). The present work points to the variable spectrum of TP53 mutations and p53 expression profile in Jordanian patients with bladder cancer and reflects the importance of p53 alterations in predicting poor prognosis of bladder cancer patients.