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Gene Expression Profiling of Progressive Papillary Noninvasive Carcinomas of the Urinary Bladder

Authors' Affiliations: ¹ Institute of Pathology and ² Department of Urology, University of Regensburg, Regensburg, Germany; ³ Institute of Clinical Genetics, Medical Faculty Carl Gustav Carus, University of Technology and ⁴ Department of Surgery, University Hospital Dresden, Dresden, Germany; ⁵ Department of Internal Medicine, Charite Campus Virchow-Klinikum, Humboldt University, Berlin, Germany; ⁶ Signature Diagnostics AG, Potsdam, Germany; ⁷ Department of Urology, Ludwig-Maximilian University, Munich, Germany; ⁸ Institute of Pathology, University of Basel, Basel, Switzerland; and ⁹ Institute of Pathology, University of Aachen, Aachen, Germany

Requests for reprints: Arndt Hartmann, Institute of Pathology, University of Regensburg, Franz-Josef-Strauss-Allee 11, D-93053 Regensburg, Germany. Phone: 49-0941-944-6605; Fax: 49-0941-944-6602; E-mail: arndt.hartmann{at}klinik.uni-r.de.

Purpose: The aim of the present study was to define gene expression profiles of noninvasive and invasive bladder cancer, to identify potential therapeutic or screening targets in bladder cancer, and to define genetic changes relevant for tumor progression of recurrent papillary bladder cancer (pTa).

Experimental Design: Overall, 67 bladder neoplasms (46 pTa, 3 pTis, 10 pT1, and 8 pT2) and eight normal bladder specimens were investigated by a combination of laser microdissection and gene expression profiling. Eight of 16 patients with recurrent noninvasive papillary bladder tumors developed carcinoma in situ (pTis) or invasive bladder cancer (pT1G2) in the course of time. RNA expression results of the putative progression marker cathepsin E (CTSE) were confirmed by immunohistochemistry using high-throughput tissue microarray analysis (n = 776). Univariate analysis of factors regarding overall survival, progression-free survival, and recurrence-free survival in patients with urothelial bladder cancer was done.

Results: Hierarchical cluster analyses revealed no differences between pTaG1 and pTaG2 tumors. However, distinct groups of invasive cancers with different gene expression profiles in papillary and solid tumors were found. Progression-associated gene profiles could be defined (e.g., FABP4 and CTSE) and were already present in the preceding noninvasive papillary tumors. CTSE expression (P = 0.003) and a high Ki-67 labeling index of at least 5% (P = 0.01) were the only factors that correlated significantly with progression-free survival of pTa tumors in our gene expression approach.

Conclusions: Gene expression profiling revealed novel genes with potential clinical utility to select patients that are more likely to develop aggressive disease.

Key Words: Bladder Neoplasms • Carcinoma • Papillary • Biological Markers • Disease Progression

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