Evaluation of Non-Invasive Assays for the Detection of Urothelial Cancer of the Bladder and Kidney

Bladder cancer is one of the most common malignancies worldwide. The rate of occurrence of these tumors is highest in the developed countries, ranking as the sixth most frequent neoplasm. Approximately 90% of malignant tumors arising in the bladder are of epithelial origin, the majority being transitional cell carcinomas. Early stage bladder tumors have been classified into two groups with distinct behaviors and different molecular profiles: Low-grade tumors (always papillary and usually superficial), and high-grade tumors (either papillary or non-papillary and often invasive). Clinically, superficial bladder tumors (stages Ta, Tis and T1) account for 75-80% of bladder neoplasms, while the remaining 15-20% are invasive (T2, T3, T4) or metastatic lesions at the time of presentation. Over 70% of patients affected with superficial tumors will have one or more recurrences after initial treatment, and about one-third of those patients will progress and eventually succumb to their disease.

Previous publications from this Urology Department have introduced the idea of a non-invasive, molecular-based assay for the detection and monitoring of bladder cancer (Levesque et al. 1993; Fitzgerald et al. 1995). At the time of publication there was limited knowledge of molecular changes underlying the different clinical pathways outlined above and our assay was based on one gene (c-H-ras-1). In the last few years, it has become clear that activation events associated with FGFR-3 can be found associated with 40%-60% of low-grade, low-stage bladder tumors whilst p53 mutations are linked to a more aggressive phenotype progressing via the CIS pathway. Mutations found in the c-H-ras-1 gene can straddle both of these groups. We propose to assess the use of a multiple mutation-based assay, using DNA from exfoliated cells in the urine of patients, to establish the sensitivity and specificity in tumor detection compared to cystoscopy and cytology. In addition, we propose to isolate free-DNA for use in molecular assays. The remaining urine will be stored to evaluate biomarkers for the detection of tumor presence or progression using protein-based analyses.

Cancer Patient Group:

All patients harboring tumors and scheduled to have a cystectomy, cystoscopy,or nephroureterectomy will be eligible for this study. This will include patients at first presentation and those who are in follow-up. Urine samples collected at the time of a procedure will be obtained from catheterized urine in the operating room. Urine obtained in the clinic setting will be obtained via voiding, as with standard urine sample collection. We propose to collect urine from study participants who have a cystoscopy on each occasion that they visit the Urology Department regarding the treatment and follow-up of their disease. The urine will be collected at intervals over a two-year period.

Control Patient Group: