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

Pfister, Christian; Flaman, Jean–Michel; Dunet, Frédérick; Grise, P.; Frébourg, Thierry

doi:10.1097/00005392-199907000-00017

Cited by 42 publications

(18 citation statements)

References 33 publications

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“…The proportion of p53 alterations detected by FASAY in T a -T 1 tumors in the present series was similar to the proportion reported by Pfister et al, 36.5% (19 of 52) versus 34% (16 of 47), respectively (22), as was the percentage of positive FASAY in invasive TCCs [83% (5 of 6) versus 100% (4 of 4), respectively], grade 2 tumors (17% versus 18%, respectively), and grade 3 tumors (79% versus 61%, respectively). However, we also compared FASAY and p53 immunohistochemistry.…”

Section: Discussionsupporting

confidence: 92%

“…To improve The critical biochemical function of p53 in carcinogenesis and tumor progression relies on alterations of the transcription of target genes controlling cell growth and apoptosis (16). Therefore, the use of a functional assay in yeast to selectively identify inactivating p53 mutations in bladder tumors, first reported by Pfister et al in 1999, seems to be a more valuable alternative to immunohistochemistry (16,21,22). In this study, the transcriptional activity of p53 was compared with p53 and p21 at the protein and gene expression levels.…”

Section: Discussionmentioning

confidence: 99%

“…The number of discordant results reported between immunohistochemistry and DNA analyses shows indeed that p53 nuclear protein accumulation cannot be considered as a reliable surrogate marker of p53 mutations and still less of its transcriptional activity (10, 13, 17 -21). The routine use of a functional assay in yeast to selectively identify inactivating p53 mutations in bladder tumors seems therefore as a better approach but still needed confirmation of its predictive value on the outcome in superficial TCCs of the bladder (21,22).…”

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confidence: 99%

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Assessment of the Transcriptional Activity of p53 Improves the Prediction of Recurrence in Superficial Transitional Cell Carcinoma of the Bladder

Dekairelle

Tombal

Cosyns

et al. 2005

Clinical Cancer Research

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Purpose:To investigate the value of p53 functional analysis of separated alleles in yeast (FASAY) as a witness of p53/p21pathway alteration and as a predictor of recurrence in superficial transitional cell carcinomas. Experimental Design: p53 transcriptional activity was prospectively analyzed in 52 newly diagnosed transitional cell carcinoma using FASAY competent for the transactivation of p21 and bax promoters.TP53 and p21gene expression was quantified by real-time PCR, and expression of corresponding proteins was assessed by immunohistochemistry. In addition to tumor stage and grade, the predictive value of FASAY, real-time PCR, and immunohistochemistry for tumor recurrence was assessed by Cox survival analysis. Results: A total (p21 and bax) or partial (bax only) loss of transcriptional activity was observed in 15 of 52 (29%) and 4 of 52 (7.7%) cases, respectively, a partial loss being consistently associated with R283H mutation. p53 nuclear overexpression grossly overestimated (f40%) or underestimated (f10%) the true incidence of p53 transcriptional abnormalities, especially inT a -T 1 grade 1 to 2 tumors. Loss of p21 transactivation significantly correlated with decreased p21 gene expression and lack of expression of p21 (P = 0.001). FASAY had a better predictive value for recurrence than p53 immunohistochemistry (Cox hazard ratio, 6.57 versus 3.95; P = 0.0002 versus 0.019, respectively), whereas neither p21 immunohistochemistry (hazard ratio, 1.9; P = 0.29) norTP53 or p21 gene expression were significant predictors of recurrence. The prognostic difference between FASAY and p53 immunohistochemistry was maintained in the subgroup of T a -T 1 grade 3 tumors. Conclusions: FASAY is a valuable surrogate marker for assessing p53/p21 pathway alteration and predicts transitional cell carcinoma recurrence better than p53 immunohistochemistry.Transitional cell carcinoma (TCC) of the bladder is the fourth most common malignancy in men and the eight most common cancer in women. Eighty percent of TCCs are initially superficial (TMN97: T a -T 1 ) and easily treated by transurethral resection of bladder tumor. Despite initial complete resection of the tumor, recurrence occurs in 30% to 90% of the cases (1, 2). Progression to muscle invasive and/or metastatic stages requires radical and/or systemic therapies in 15% to 20% of the cases. To decrease recurrence and progression rates, intravesical administration of chemotherapy and/or Bacillus CalmetteGuerin is considered as standard therapy (2, 3). Because these therapies are not devoid of local and systemic toxicity, their use should better be guided by individual risks for recurrence and progression (4).Over the years, many attempts have been made to identify molecular markers that would supersede clinical features, such as tumor stage, grade, and multifocality (5, 6). Expression of TP53 gene has been one of the most frequently assessed genetic alterations in bladder TCC. In an overwhelming majority of studies, the prognostic significance of TP53 alterations in...

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Section: Discussionsupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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Assessment of the Transcriptional Activity of p53 Improves the Prediction of Recurrence in Superficial Transitional Cell Carcinoma of the Bladder

Dekairelle

Tombal

Cosyns

et al. 2005

Clinical Cancer Research

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“…Subsequently, Pfister and coworkers prospectively reviewed 60 superficial bladder tumors and reported that a significant percentage of high-grade tumors had been shown to have the p53 mutation in contrast to low-grade tumors [49]. They found that p53 was significantly associated with a BCG-refractory phenotype.…”

Section: Prognostic Factorsmentioning

confidence: 99%

Controversial issues and optimal management of stage T1G3 bladder cancer

Metwalli¹,

Kamat²

2006

Expert Review of Anticancer Therapy

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The management of T1G3 bladder cancer is controversial. Diagnostic methods, such as bladder mapping or second-look transurethral resection are recommended to assess risk. Bacillus Calmette-Guérin intravesical therapy with a maintenance regimen is recommended for solitary T1G3 tumors. The timing of radical cystectomy for these patients is controversial, but early recurrence during intravesical therapy is an indication for radical cystectomy. Multifocal disease, concomitant carcinoma in situ and disease in the prostatic urethra and bladder neck also suggest aggressive disease and cystectomy should be considered in these patients.

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“…It has been reported that in superficial bladder cancers, p53 mutations may inactivate the transcription of bax gene. 26 Bax is a member of the bcl-2 family and has a pro-apoptotic effect. 27 Although the phenomenon of p53 overexpression in TCC has mostly been reported to have underlying genetic mutations, 28 the authors can not conclude that the p53 positivity observed in our cases are accompanied by p53 mutation, and hence the exact role of mutant and/or wild-type p53 expression on frequency of apoptosis and bcl-2 in TCC requires more studies.…”

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confidence: 99%

Apoptosis in transitional cell carcinoma of bladder and its relation to proliferation and expression of P53 and Bcl-2

Amirghofran

Monabati

Khezri

et al. 2004

Pathol. Oncol. Res.

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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

Abstract: 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.

Cited by 42 publications

References 33 publications

Assessment of the Transcriptional Activity of p53 Improves the Prediction of Recurrence in Superficial Transitional Cell Carcinoma of the Bladder

Assessment of the Transcriptional Activity of p53 Improves the Prediction of Recurrence in Superficial Transitional Cell Carcinoma of the Bladder

Controversial issues and optimal management of stage T1G3 bladder cancer

Apoptosis in transitional cell carcinoma of bladder and its relation to proliferation and expression of P53 and Bcl-2

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