UroToday - The function of the normal product of the TP53 gene, the p53 protein, forms the crucial basis of normal cell biology; conversely, the dysfunction of its mutant protein product underlies altered cellular response in cancer. One reason why the protein accumulates in human tumors is that wild-type p53 has a very short half-life (approximately 20 to 30 minutes), whereas mutant p53 proteins often have a much longer half-life (approximately 24 hours). In normal cells, responding to a variety of cellular stresses such as genome damage, wild-type p53 is activated by multiple post-translational mechanisms, including its phosphorylation. Stabilized phospho-p53 accumulates in cells, and can reach sufficient levels to regulate its target genes. p53 can then activate a transient cell cycle arrest pathway to allow recovery from the causative stress, followed by subsequent cell cycle progression; or an apoptotic program that helps avoid the accumulation of genomic damage. In cancer cells, loss of function of p53 compromises these crucial processes. Inactivation (loss of function) of Tp53 is shown to occur mainly through point mutations, leading to amino acid substitutions (missense mutations), or in some cases a truncated nonfunctional protein due to premature stop codons. Although a handful of hotspot codons account for 30% of all mutations, the remaining 70% are distributed widely. Thus, the interpretation of Tp53 mutation (and p53 overexpression) data can be very complex because different mutants display distinct functional properties. The heterogeneity of mutations provides the basis for a more thorough analysis of the biologic and clinical significance of each mutation.

We have queried the entire coding sequence of the Tp53 gene using GeneChip analysis of archival tumor DNA in the present publication and report on the role of p53 alterations in predicting outcome of patients with bladder cancer undergoing radical cystectomy. Importantly, both Tp53 gene status as well as p53 protein expression were assessed in the tumors of 150 patients. In concordance with other published studies, the concordance of both analyses was incomplete. Remarkably, we found that tumors with exon 5 mutations more commonly displayed normal p53 immunostaining, in contrast with the remaining Tp53 mutant tumors; these exon 5 mutations were also more commonly found in tumors confined to bladder. These observations are novel in the bladder cancer literature. We also examined the added value of information on Tp53 mutations and protein status when analyzing association with outcome. It was seen that patients with abnormal findings in both protein and DNA assays had the worst prognosis, those with normal findings in both assays had the best prognosis, and those with one abnormal and one normal finding had an intermediate probability of recurrence and survival. We therefore propose that both types of assays should be performed to better establish the prognosis of patients with advanced bladder tumors.

This is one of the largest reports on Tp53 gene and protein status in muscle-invasive tumors. Nevertheless, we recognize that the number of patients in each subgroup is small, limiting the statistical conclusions. Therefore, in order for this striking evidence to change the present clinical practice going forward, it is imperative that prospective, multicenter clinical trials be performed and carried out in the context of uniform patient management. Through the prospectively designed clinical trial (p53 Targeted Therapy Trial), we have paved the path to determine whether stratification by Tp53 status can impact the management of patients with advanced bladder cancer. This ongoing study is based on the relationship between p53 alterations, progression, and response to chemotherapy. As the editorial commentary by Dr. Real accompanying the publication in JCO states, our findings should stimulate more work on p53 in bladder cancer, with future multicenter studies aiming at determining whether mutations in specific Tp53 exons and in specific codons bear distinct prognostic or predictive value. Tp53 mutations have a potential to impinge on resistance to therapy, and detailed information on treatment and therapeutic response should be gathered. In our present study, we speculate that the site of the mutation could also influence the response to therapy, an idea that needs further investigation. As Dr. Real accurately points out, 'unless we perform studies with markers of outcome in a more efficient manner, interesting important assays and markers will not make it to the clinic and much may be lost in translational research'.



Ram H. Datar, MD and Richard J. Cote, MD, Department of Pathology, University of Southern California Keck School of Medicine, Los Angeles, CA, as part of Beyond the Abstract on UroToday. This initiative offers a method of publishing for the professional urology community. Authors are given an opportunity to expand on the circumstances, limitations etc... of their research by referencing the published abstract.

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