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

Abstract

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 (zpT1G2) 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.At the time of first diagnosis, f70% of bladder tumors are noninvasive papillary low-grade tumors (pTa). However, >60% of these tumors will recur at least once and progress to infiltrating or less differentiated neoplasms in 5% to 10% of cases (1). Despite the fact that the majority of superficial bladder tumors are clinically benign, regular cystoscopic follow-up at intervals is done in all patients with noninvasive bladder cancer after complete transurethral resection to detect recurrence and progression. A plethora of potential clinical and histopathologic factors indicative of tumor progression are currently discussed in the context of papillary bladder cancer: high tumor grade (2), tumor size of >5 cm (3), multifocality (4), adjacent carcinoma in situ (5), and high rate of recurrence. However, none of these markers reliably predicts a higher progression rate in papillary carcinoma of the bladder (pTa). It is important to identify the small subgroup of patients that will most likely benefit from close clinical follow-up and Bacillus Calmette-Guerin instillation therapy. New molecular prognostic markers for the prediction of tumor recurrence and progression are urgently needed.Mutations of the tumor suppressor genes TP53 and RB1 are common and have predictive va...

Molecular characterization of early-stage bladder carcinomas by expression profiles, FGFR3 mutation status, and loss of 9q

“…This was also shown by the finding that Clusters I and II overlapped in the MDS indicating a continuous change in expression levels, even though the HCA revealed Cluster I tumors as a distinct subtype. Furthermore, and as previously shown (Wild et al, 2005), we could not find any genes that distinguished G1 from G2 tumors, again underscoring the continuous transition from one state to another. These findings may limit the possibility to define distinct clinical categories of Ta tumors based on expression patterns only.…”

“…FGFR3 expression showed an inverse relationship with grade/stage, also noted by other investigators (Dyrskjt et al, 2005;Wild et al, 2005). The distribution of the expression levels was, however, not normally distributed suggesting the presence of two categories of UCCs, one showing high and one low FGFR3 expression.…”

“…In recent years, genome-wide expression profiling by the use of microarray technology has contributed to extensive and new insights into the complex gene expression patterns and dysregulation of genes occurring in urothelial neoplasias (Thykjaer et al, 2001;Dyrskjt et al, 2003Dyrskjt et al, , 2004Dyrskjt et al, , 2005Mor et al, 2003;SanchezCarbayo et al, 2003;Modlich et al, 2004;Blaveri et al, 2005;Kim et al, 2005;Wild et al, 2005). Microarray analyses have not only delineated gene expression profiles distinct for different histological subtypes (Thykjaer et al, 2001;Dyrskjt et al, 2003Dyrskjt et al, , 2004Sanchez-Carbayo et al, 2003;Blaveri et al, 2005;Wild et al, 2005), but also gene expression signatures of importance for tumor recurrence and progression (Dyrskjt et al, 2003(Dyrskjt et al, , 2005Modlich et al, 2004;Wild et al, 2005), and patient survival (Blaveri et al, 2005;Kim et al, 2005).…”

“…Microarray analyses have not only delineated gene expression profiles distinct for different histological subtypes (Thykjaer et al, 2001;Dyrskjt et al, 2003Dyrskjt et al, , 2004Sanchez-Carbayo et al, 2003;Blaveri et al, 2005;Wild et al, 2005), but also gene expression signatures of importance for tumor recurrence and progression (Dyrskjt et al, 2003(Dyrskjt et al, , 2005Modlich et al, 2004;Wild et al, 2005), and patient survival (Blaveri et al, 2005;Kim et al, 2005). Whereas previous microarray studies of bladder cancer mostly have been dedicated to isolate gene expression profiles and predictors that classify tumors according to stage, recurrence and outcome, we focus on a comprehensive molecular characterization of Ta and T1 tumors.…”

Prediction of recurrence in Ta urothelial cell carcinoma by real‐time quantitative PCR analysis: A microarray validation study

“…[34][35][36][37][38] Therefore, it may not be surprising that these tumors also have largely similar gene expression profiles. 39 Consequently, the accurate distinction between Ta tumors derived from patients with delayed recurrences and patients with early recurrences by investigating gene expression profiles poses a challenge.…”