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The p53 Pathway and Outcome among Patients with T1G3 Bladder Tumors

Authors' Affiliations: ¹ Institut Municipal d'Investigació Mèdica, ² Universitat Pompeu Fabra, and ³ Hospital del Mar, Barcelona, Spain; ⁴ Universidad de Oviedo, Oviedo, Spain; ⁵ Hospital General Universitario, Instituto de Biología Molecular y Celular, Universidad Miguel Hernández, Elche, Spain; and ⁶ Corporació Sanitària Parc Tauli, Sabadell, Spain

Requests for reprints: Francisco X. Real, Institut Municipal d'Investigació Mèdica, Universitat Pompeu Fabra, Carrer del Dr. Aiguader 80, 08003-Barcelona, Spain. Phone: 34-93-2211009; Fax: 34-93-2216448; E-mail: preal{at}imim.es.

Purpose: The aim was to analyze Tp53 and HDM2 in T1G3 bladder tumors and to determine the prognostic value of their alterations.

Experimental Design: Tumors (n = 119) were extracted from a prospective study of 1,356 bladder cancers. Tp53 mutations (exons 4-9) were assessed by sequencing of PCR products. HDM2 dose was assessed by quantitative PCR. p53, HDM2, and the products of p53 target genes were analyzed by immunohistochemistry. Cases were distributed in three categories. The association with prognosis was determined using Kaplan-Meier and Cox analyses.

Results: Eighty-five percent of tumors harbored alterations in Tp53 or HDM2. In group 1 (n = 77), 69 tumors had inactivating Tp53 mutations (58%), and 8 had HDM2 gains (7%). Group 2 (n = 24) comprised tumors overexpressing p53 in the absence of mutations (20%). Group 3 tumors (n = 18) had no alterations. HDM2 gains were associated to HDM2 overexpression and to wild-type Tp53. Expression of type 1 insulin-like growth factor receptor, 14-3-3 , and cyclooxygenase-2 was similar in groups 1 and 2 and significantly different from group 3. Survivin was expressed in the majority of tumors regardless of p53 pathway status. Taking group 3 as reference, the hazard ratios (HR) for recurrence, progression, and death were not significantly different in the other patient groups. HRs for recurrence were 1.13 for group 1 [95% confidence interval (95% CI), 0.25-5.03] and 1.40 for group 2 (95% CI, 0.27-7.20). HRs for progression were 0.50 for group 1 (95% CI, 0.18-1.40) and 0.25 for group 2 (95% CI, 0.05-1.29).

Conclusions: The p53 pathway is inactivated in most T1G3 bladder tumors. These genetic alterations do not independently predict patient's prognosis.

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