Abstract
New markers that enable the percentage of transitional cell carcinomas (TCC) of the bladder that are diagnosed before invasion of the bladder muscle layers to be increased would reduce the morbidity and mortality associated with this disease. The purpose of this study was to develop a simple, accurate urine test based on mRNA markers and simple gene signatures that (a) could detect TCC before muscle invasion while maintaining high specificity in patients with hematuria or urinary tract infections and (b) identify patients most likely to have grade 3 or stage > or =T1 disease. RNA markers with high overexpression in stage Ta tumors and/or T1 to T4 tumors but low expression in blood or inflammatory cells were characterized by quantitative reverse transcription-PCR using 2 mL of voided urine from 75 TCC patients and 77 control patients with other urological diseases. A combination of the RNAs CDC2, MDK, IGFBP5, and HOXA13 detected 48%, 90%, and 100% of stage Ta, T1, and >T1 TCCs, respectively, at a specificity of 85%. Detection of Ta tumors increased to 60% for primary (non-recurrent) Ta tumors and 76% for Ta tumors > or =1 cm in diameter. Test specificity was 80% for the 20 control patients with urinary tract infections. The combination of CDC2 and HOXA13 distinguished between grade 1 to 2 TCCs and grade 3 or stage > or =T1 TCCs with approximately 80% specificity and sensitivity. Simple gene expression signatures can be used as urine markers for the accurate detection and characterization of bladder cancer.
Highlights
New markers that enable the percentage of transitional cell carcinomas (TCC) of the bladder that are diagnosed before invasion of the bladder muscle layers to be increased would reduce the morbidity and mortality associated with this disease
We hypothesized that mRNAs with high overexpression in transitional cell carcinomas (TCC) compared with normal urothelium and low expression in blood and inflammatory cells would constitute sensitive urine markers that showed high specificity in patients presenting with hematuria or urinary tract infections
The array data for genes with high overexpression in either stage Ta or T1 to T4 tumors were validated by quantitative reverse transcriptionPCRs (qRT-PCR) (Table 1) using RNA extracted from 18 normal urothelium samples and up to 28 Ta tumors and 30 stage T1 to T4 tumors
Summary
New markers that enable the percentage of transitional cell carcinomas (TCC) of the bladder that are diagnosed before invasion of the bladder muscle layers to be increased would reduce the morbidity and mortality associated with this disease. Recent studies using high-throughput microarray analysis have shown that mRNA expression profiles are a powerful method for discriminating between bladder tumors and normal urothelium and defining subgroups of bladder tumors [5,6,7,8] The informativeness of these expression profiles and the high frequency of tumor cell exfoliation into urine have raised the prospect of using simple gene expression signatures obtained from urine total RNA to better diagnose bladder cancer and provide more information on disease characteristics at the time of diagnosis. We hypothesized that mRNAs with high overexpression in transitional cell carcinomas (TCC) compared with normal urothelium and low expression in blood and inflammatory cells would constitute sensitive urine markers that showed high specificity in patients presenting with hematuria or urinary tract infections. We describe the selection and validation of mRNA markers for the detection of TCC that are significantly overexpressed
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