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.
OBJECTIVE
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.


METHODS
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).


RESULTS
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.


CONCLUSIONS
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.
Pfister
C
C
Service d'Urologie, Laboratoire de Génétique Moléculaire, CHU de Rouen, Génétique et Hématologie Moléculaires, IFRMP, Mont St Aignan, France.
Flaman
J M
JM
Dunet
F
F
Grise
P
P
Frebourg
T
T
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001500:BCG Vaccine / Q000627:therapeutic use*; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000235:genetics*; D004791:Enzyme Inhibitors; D016158:Genes, p53 / Q000235:genetics*; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009367:Neoplasm Staging; D011237:Predictive Value of Tests; D011446:Prospective Studies; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D016896:Treatment Outcome; D001749:Urinary Bladder Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy*; D051028:bcl-2-Associated X Protein
D000276:Adjuvants, Immunologic; C494826:BAX protein, human; D001500:BCG Vaccine; C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D004791:Enzyme Inhibitors; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; D051028:bcl-2-Associated X Protein