Bladder cancer: translating molecular genetic insights into clinical practice

Transitional cell (urothelial) carcinoma of the bladder is the second most common urologic malignancy and is one of the best understood neoplasms, with relatively well-defined pathogenetic pathways, natural history, and tumor biology. Conventional clinical and pathologic parameters are widely used to grade and stage tumors and to predict clinical outcome of transitional cell carcinoma; but the predictive ability of these parameters is limited, and there is a lack of indices that could allow prospective assessment of risk for individual patients. In the last decade, a wide range of candidate biomarkers representing key pathways in carcinogenesis have been reported to be clinically relevant and potentially useful as diagnostic and prognostic molecular markers, and as potential therapeutic targets. The use of molecular markers has facilitated the development of novel and more accurate diagnostic, prognostic, and therapeutic strategies. FGFR3 and TP53 mutations have been recognized as key genetic pathways in the carcinogenesis of transitional cell carcinoma. FGFR3 appears to be the most frequently mutated oncogene in transitional cell carcinoma; its mutation is strongly associated with low tumor grade, early stage, and low recurrence rate, which confer a better overall prognosis. In contrast, TP53 mutations are associated with higher tumor grade, more advanced stage, and more frequent tumor recurrences. These molecular markers offer the potential to characterize individual urothelial neoplasms more completely than is possible by histologic evaluation alone. Areas in which molecular markers may prove valuable include prediction of tumor recurrence, molecular staging of transitional cell carcinoma, detection of lymph node metastasis and circulating cancer cells, identification of therapeutic targets, and prediction of response to therapy. With accumulating molecular knowledge of transitional cell carcinoma, we are closer to the goal of bridging the gap between molecular findings and clinical outcomes. Assessment of key genetic pathways and expression profiles could ultimately establish a set of molecular markers to predict the biological nature of tumors and to establish new standards for molecular tumor grading, classification, and prognostication. The main focus of this review is to discuss clinically relevant biomarkers that might be useful in the management of transitional cell carcinoma and to provide approaches in the analysis of molecular pathways that influence the clinical course of bladder cancer.