Distinct Expression Profiles of p63 Isoforms during Bladder Cancer Progression.
Mireia Castillo-Martin, Orit Karni-Schmidt, Nataliya Gladoun, Josep Domingo-Domenech, Carlos Cordon-Cardo. Columbia University, New York, NY
Background: The TP63 gene is expressed as at least six different isoforms due to alternative promoter usage. p63 expression has previously been correlated with bad prognosis in bladder cancer. Nevertheless, the lack of p63 isoform-specific antibodies has limited the understanding of their biological significance and clinical implications.
Design: We analyzed 10 normal bladders and 202 bladder cancers, distributed as follows: 147 "superficial" UC (31 pTa and 116 pT1) and 55 "invasive" UC, pT2+ (22 pT2, 23 pT3 and 10 pT4). Follow-up clinical data was available from 183 patients. Immunohistochemistry and Immunofluorescence were performed following standard protocols, using newly generated and commercially available antibodies.
Results: As expected, basal and intermediate cells of normal urothelium displayed nuclear expression of total p63, which corresponded to TAp63α. 96.8% of the pTa cases and 94.0% of the pT1 cases showed expression of total p63, whereas only 69.1% of the invasive pT2+ bladder cancers expressed total p63. On the contrary, ΔNp63 was undetectable in normal bladder urothelium, whereas it was expressed in 29% of the pTa, 17.2% of the pT1 and 41.8% of the pT2+ bladder tumors. Patients whose tumors displayed a total p63 positive phenotype had a better prognosis than those from whom their tumors had a p63 negative phenotype, with a longer disease specific survival (p< 0.0001). Since total p63 expression is correlated with tumor stage, we evaluated the clinical implications of p63 expression in "invasive" and "superficial" carcinomas separately. Total p63 and ΔNp63 expression showed significant prognostic connotations in "superficial" tumours, since patients with a negative phenotype showed a higher recurrence rate (p<0.05 and p<0.01, respectively). On the contrary, ΔNp63 was a marker of poor prognosis in invasive carcinoma, since patients whose tumors showed a ΔNp63 positive phenotype had a shorter survival (p< 0.05). Moreover, we observed a direct correlation between ΔNp63 and high molecular weight CKs (HMWCK) expression (p<0.01), and an inverse correlation with CK20 (p<0.05). Finally, and also importantly, we observed a correlation between expression of ΔNp63 and p53 mutation (p<0.001).
Conclusions: This study highlights the relevance of p63 isoforms in bladder carcinoma progression. We propose a new categorization of invasive bladder cancer into “basal-like” (ΔNp63 and HMWCK positive; CK20 negative) versus “luminal-like” (ΔNp63 and HMWCK negative; CK20 positive), being ΔNp63 expression associated with mutation of p53 and an aggressive clinical outcome.
Category: Genitourinary (including renal tumors)
Tuesday, March 1, 2011 9:30 AM
Poster Session III # 174, Tuesday Morning