<i>p53</i> Gene and Protein Status: The Role of <i>p53</i> Alterations in Predicting Outcome in Patients With Bladder Cancer

George, Ben; Datar, Ram H.; Wu, Lin; Cai, Jie; Patten, Nancy; Beil, Stephen; Groshen, Susan; Stein, John P.; Skinner, Donald G.; Jones, Peter A.; Côté, Richard J.

doi:10.1200/jco.2006.10.4125

Cited by 116 publications

(72 citation statements)

References 33 publications

(4 reference statements)

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“…On the contrary, ⌬Np63 protein levels showed the opposite trend: 41.8% of invasive carcinomas displayed a positive phenotype, whereas only 19.7% of the non-muscle invasive cancers showed expression of ⌬Np63. Moreover and as expected, p53 expression levels, which are known to correlate with mutated TP53, 37,38 were also significantly higher in the invasive tumors when compared with non-muscle invasive neoplasms (43.6% vs 20.4%). Thus, these results highlight the importance of determining which p63 isoforms are expressed in the distinct bladder cancer stages because total p63 evaluation may lead to erroneous conclusions.…”

Section: ⌬Np63 and Mutant P53 Are Associated With Bladder Cancer Tumosupporting

confidence: 82%

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Karni-Schmidt

Castillo-Martín

HuaiShen

et al. 2011

The American Journal of Pathology

120

112

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The TP63 gene, a member of the TP53 tumor suppressor gene family, can be expressed as at least six isoforms due to alternative promoter use and alternative splicing. The lack of p63 isoform-specific antibodies has limited the analysis of the biological significance of p63. We report a novel set of well-defined antibodies to examine p63 isoforms in mouse and human urothelium during embryogenesis and tumor progression, respectively. We provide evidence that basal and intermediate urothelial cells express p63 isoforms, with the TAp63 variant the first to be detected during development, whereas umbrella cells are characterized by a p63-negative phenotype. Notably, we report that p63-null mice develop a bladder with an abnormal urothelium, constituted by a single layer of cells that express uroplakin II and low molecular weight cytokeratins, consistent with an umbrella cell phenotype. Finally, analysis of 202 human bladder carcinomas revealed a new categorization of invasive tumors into basal-like (positive for ⌬Np63 and high molecular weight cytokeratins and negative for low molecular weight cytokeratins) versus luminal-like (negative for ⌬Np63 and high molecular weight cytokeratins and positive for low molecular weight cytokeratins) phenotypes, with ⌬Np63 expression associated with an aggressive clinical course and poor prognosis. This study highlights the relevance of p63 isoforms in both urothelial development and bladder carcinoma progression, with ⌬Np63 acting as an oncogene in certain invasive bladder tumors.

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Section: ⌬Np63 and Mutant P53 Are Associated With Bladder Cancer Tumosupporting

confidence: 82%

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Karni-Schmidt

Castillo-Martín

HuaiShen

et al. 2011

The American Journal of Pathology

120

112

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“…These included single cases of urethral hyperplasia, urethral carcinoma, and ureteral and renal carcinomas that expressed higher levels of protein by IHC. These types of discordant results have been reported previously and are likely either the result of gene mutations occurring in unsequenced exons or a reflection of a low percentage of mutation-positive tumor cells (Bian et al 2001;Kropveld et al 1996;George et al 2007).…”

Section: Discussionsupporting

confidence: 81%

Mutation Spectra of Kras and Tp53 in Urethral and Lung Neoplasms in B6C3F1 Mice Treated with 3,3′,4,4′-Tetrachloroazobenzene

et al. 2013

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3,30 ,4,4 0 -tetrachloroazobenzene (TCAB) is a contaminant formed during manufacture of various herbicide compounds. A recent National Toxicology Program study showed B6C3F1 mice exposed to TCAB developed a treatment-related increase in lung carcinomas in the high-dose group, and urethral carcinomas, an extremely rare lesion in rodents, in all dose groups. As the potential for environmental exposure to TCAB is widespread, and the mechanisms of urethral carcinogenesis are unknown, TCAB-induced urethral and pulmonary tumors were evaluated for alterations in critical human cancer genes, Kras and Tp53. Uroplakin III, CK20, and CK7 immunohistochemistry was performed to confirm the urothelial origin of urethral tumors. TCAB-induced urethral carcinomas harbored transforming point mutations in K-ras (38%) and Tp53 (63%), and 71% displayed nuclear TP53 expression, consistent with formation of mutant protein. Transition mutations accounted for 88% of Tp53 mutations in urethral carcinomas, suggesting that TCAB or its metabolites target guanine or cytosine bases and that these mutations are involved in urethral carcinogenesis. Pulmonary carcinomas in TCAB-exposed animals harbored similar rates of Tp53 (55%) and Kras (36%) mutations as urethral carcinomas, suggesting that TCAB may induce mutations at multiple sites by a common mechanism. In conclusion, TCAB is carcinogenic at multiple sites in male and female B6C3F1 mice through mechanisms involving Tp53 and Kras mutation.

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“…[25][26][27] Among these exons, 5 and 8 contain the majority of mutations. 28 We focused our screening on exons 5, 7 and 8 allowing us to screen those exons most likely to harbor mutations without significantly decreasing our sensitivity. However, the possibility of additional mutations in less common regions cannot be ruled out.…”

Section: Discussionmentioning

confidence: 99%

TP53 mutational analysis supports monoclonal origin of biphasic sarcomatoid urothelial carcinoma (carcinosarcoma) of the urinary bladder

et al. 2009

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Sarcomatoid urothelial carcinoma of the urinary bladder is an uncommon neoplasm with biphasic morphology exhibiting both epithelial and sarcomatoid components. Whether this tumor arises from a single cancer stem cell with subsequent differentiation or represents collision of the progeny of two separate cancer stem cells is a matter of controversy. To clarify its clonal origin, we analyzed the TP53 mutation status of a series of 17 sarcomatoid urothelial carcinomas using single-strand conformation polymorphism, DNA sequencing and p53 immunohistochemistry. Sarcomatoid and epithelial tumor components were separately microdissected using laser capture microdissection. Five out of the 17 sarcomatoid urothelial carcinomas contained TP53 point mutations in exons 5 and 8. In all five cases, the TP53 point mutations were identical in both the epithelial and sarcomatoid components. The sarcomatoid and epithelial tumor components in all 17 cases showed concordant p53 expression patterns. Our results suggest that despite their conspicuous divergence at the phenotypic level, the sarcomatoid and carcinomatoid elements of this uncommon tumor share a common clonal origin.

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p53 Gene and Protein Status: The Role of p53 Alterations in Predicting Outcome in Patients With Bladder Cancer

Cited by 116 publications

References 33 publications

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Distinct Expression Profiles of p63 Variants during Urothelial Development and Bladder Cancer Progression

Mutation Spectra of Kras and Tp53 in Urethral and Lung Neoplasms in B6C3F1 Mice Treated with 3,3′,4,4′-Tetrachloroazobenzene

TP53 mutational analysis supports monoclonal origin of biphasic sarcomatoid urothelial carcinoma (carcinosarcoma) of the urinary bladder

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