Molecular alterations associated with bladder cancer initiation and progression

Bladder cancer is the fifth most commonly diagnosed non-cutaneous solid malignancy, and the second most commonly diagnosed genitourinary malignancy amongst people living in the United States, where it is estimated that more than 61,000 new cases of bladder cancer will be diagnosed in the year 2008. Approximately 90% of malignant tumors arising in the urinary bladder are of epithelial origin, the majority being transitional cell carcinomas. Early stage bladder tumors have been classified into two groups with distinct behavior and unique 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 and Tis) account for 75% to 85% of neoplasms, while the remaining 15% to 25% are invasive (T1, T2-T4) or metastatic lesions at the time of initial presentation. Studies from the author's group and others have revealed that distinct genotypic and phenotypic patterns are associated with early versus late stages of bladder cancer. Most importantly, early superficial diseases appear to segregate into two main pathways. Superficial papillary bladder tumors are characterized by gain-of-function mutations, mainly affecting classical oncogenes such as RAS and FGFR3. Deletions of chromosome 9, mainly allelic losses on the long arm (9q) are also frequent events in these tumors. Such genetic alterations are observed in most if not all superficial papillary non-invasive tumors (Ta), but only in a small subset of invasive bladder neoplasms. Flat carcinoma in situ (Tis) and invasive tumors are characterized by loss-of-function mutations, affecting the prototype tumor suppressor genes, including p53, RB and PTEN. These alterations are absent or very rare in the Ta tumors analyzed, but have been frequently identified in invasive bladder carcinomas. Based on these data, a novel model for bladder tumor progression has been proposed in which two separate genetic pathways characterize the evolution of superficial bladder neoplasms. Numerous individual molecular markers have been identified in the tissue specimens that correlate to some extent with tumor stage, and possibly with prognosis in bladder cancer. However, these molecular prognosticators do not play a role in the clinical routine management of patients with bladder tumors, mainly due to lack of large prospective validation studies. Thus, the need for development of specific tissue and serum tumor markers for prognostic stratification remains. The advent of high-throughput microarrays technologies allows comprehensive discovery of targets relevant in bladder cancer progression, which could be translated into new approaches for drug and biomarker development. Further investigation is warranted to define novel biomarkers specific for bladder cancer patients based on the molecular alterations of tumor progression, and multiplexed strategies for clinical management.