P53 MUTATIONS IN BLADDER TUMORS INACTIVATE THE TRANSACTIVATION OF THE P21 AND BAX GENES, AND HAVE A PREDICTIVE VALUE FOR THE CLINICAL OUTCOME AFTER BACILLUS CALMETTE-GUERIN THERAPY

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Abstract
We analyze the relationship among p53 mutations, p21 and Bax activation as well as their clinical implication in clinical response to intravesical bacillus Calmette-Guerin (BCG) therapy in high grade bladder tumors. We analyzed a prospective series of 60 superficial bladder tumors using functional assays in yeast which test the transcriptional competence of p53 and can be used to identify p21 and Bax status. BCG instillations were given after initial tumor resection to 26 patients with a high risk of bladder invasive disease (pT1G3 tumors in 24 and carcinoma in situ in 2). No p53 alteration was detected in cases of pTa tumors. In contrast, p53 mutations were detected in 16 of 24 patients (66%) with pT1 G3 tumors and in 2 with primary carcinoma in situ. These 18 mutant samples scored also mutant for transactivation of p21 and Bax reporter strain. In 26 bladder tumors treated with BCG instillations there was a statistical difference (p = 0.0075) in the response to BCG therapy between 18 tumors with and 8 without alterations using functional assays in yeast. The p53 mutations, using functional assay in yeast, inactivate the transcription of p21 and Bax genes, and based on these preliminary results could have a useful predictive value for BCG therapy response in bladder cancer.