p53 Mutations and Prognosis in Bladder Tumors

Abstract

The incidence of loss of heterozygosity on chromosome 17p and p53 gene mutations was assessed in 43 bladder tumor patients. Histological findings, cigarette smoking and prognosis were examined for possible correlation with the presence or absence of loss of heterozygosity on 17p and p53 mutations. Of 20 informative cases 10 (50.0%) showed loss of heterozygosity of 17p13, including 9 (90.0%) with disease beyond stage pT2. The p53 mutations were detected in 20 of 43 patients (46.5%), including 9 (95.0%) with disease beyond grade 2 and 17 (85.0%) with cancer beyond stage pT2. The incidence of p53 gene mutations was not significantly influenced by habitual smoking but G:C to T:A substitutions, often observed in lung cancers, were detected only in mutations from smokers (5 of 10 or 50%, p < 0.05). Groups with and without loss of heterozygosity showed essentially the same results, while significant differences were found for groups with grades 1 and 2 to 3 (p < 0.05) cancer, stages pT1 and pT2 to 4 (p < 0.01) disease, and with and without p53 gene mutations (p < 0.01, Cox-Mantel test). Genetic alternation in chromosome 17p and p53 mutations would, thus, appear to occur more frequently in high grade and invasive bladder tumors. Cigarette smoking may possibly be a determining factor of mutations of the p53 gene in bladder tumors. Our results indicate that an unfavorable prognostic factor may possibly be linked not only to histopathological findings but the presence of a p53 mutation in bladder tumors as well. Accordingly, mutations of the p53 gene may be deeply involved in late events of tumorigenesis and possibly useful as ideal molecular markers for prognosis in bladder tumors.

Cigarette smoking and p53 mutations in lung cancer and bladder cancer.

“…The few nonsmoker cases reported at this time show an overall level of mutations comparable to, but a base substitution pattern deviant from, that in smokers (21). Nuclear overexpression or mutations have been found in 40 to 45% of bladder tumors from smokers and at a lower level (30-35%) among ex-smokers and nonsmokers in many (12,22) but not all (23) studies.…”

Frequent and heterogenous expression of cyclin-dependent kinase inhibitor WAF1/p21 protein and mRNA in urothelial carcinoma

“…Accordingly, when averaged across all tumour stages, increased p21 expression did not correlate with either the presence or the absence of p53 accumulation (Table 3). In urothelial carcinoma accumulation of p53 protein, particularly in advanced tumours, is usually due to mutations in the gene (Cordon-Cardo et al, 1994;Williamson et al, 1994;Grimm et al, 1995;Uchida et al, 1995;Vet et al, 1995). This suggests that in the majority of tumours staining positive for both proteins, p21 was not induced by p53.…”

“…Genes involved in cell cycle control and affected in urothelial carcinoma comprise MTSJ/p16 and MTS2/p15 encoding inhibitors of cyclin-dependent kinases (CDKs) (Orlow et al, 1995), cyclin Dl (Bringuier et al, 1994), RB (Xu et al, 1993) and MYC (Lipponen, 1995;Schmitz-Drager et al, 1996). In addition, depending on stage and grade, a considerable fraction of urothelial carcinomas display accumulation of p53 protein usually due to point mutations in the gene (Wright et al, 1991;Cordon-Cardo et al, 1994;Esrig et al, 1994;Schmitz-Drager et al, 1994;Williamson et al, 1994;Uchida et al, 1995;Vet et al, 1995).…”

TP53 mutational analysis supports monoclonal origin of biphasic sarcomatoid urothelial carcinoma (carcinosarcoma) of the urinary bladder

“…TP53 sequences in exons 5, 7 and 8 were amplified by hot-start PCR using the primers listed in Table 1. 18,19 TP53 sequences were amplified using 3 ml of genomic DNA, 2.3 mM MgCl 2 , 10 mM Tris-HCl (pH 8.3), 50 mM KCl, 0.2 mM deoxynucleotide triphosphates, 0.8 mCi a-32 PdATP, 0.33 mM of each primer and 1 unit of Taq DNA polymerase (Bio-Rad, Hercules, CA, USA) with a final volume of 25 ml. Each PCR protocol had an initial denaturing step of 951C for 5 min, followed by 35 cycles at 951C for 30 s, 551C for 30 s and 721C for 30 s, which was then followed by a single final extension step at 721C for 7 min.…”