Bladder cancer remains an important public-health problem with more 54,000 individuals predicted to be diagnosed in 1997. Despite important advances, approximately one half of the patients diagnosed with superficial disease will suffer a recurrence, and these patients have a significant risk for developing muscle invasive disease. Cystectomy is generally required for muscle invasive disease. Identification of individuals at high risk for recurrence and progression is thus critical, but current clinical markers are imperfect. Prevention of the dire consequences of disease progression is an even more desirable goal. To this end, a number of putative chemopreventive agents have been identified. Clinical investigation and development of these agents is, however, limited by lack of markers to determine efficacy. Thus, th purpose of this proposal is to identify and develop markers based on the known disease biology that may be intermediate markers for chemoprevention studies. Three such markers will be evaluated here. The first is deletion of the 9p21 chromosomal region as determined by fluorescence in situ hybridization (FISH). These deletions are the most common and earliest identifiable genetic alteration in bladder cancer. The second is overexpression of the epidermal growth factor receptor (EGFR). Such overexpression has been identified in the histologically normal tissue of patients with bladder cancer. The final marker is 8-OH-deoxyguanosine (8-OHdG). This marker of oxidative DNA damage has been reported to be elevated in the urine of tobacco abusers, and bladder cancer is a tobacco-related disease. The eventual goal is to develop markers that are easily measured in the urine or in bladder wash specimens. In this proposal, measurements for each marker will be determined in such samples and compared to measurements in normal and malignant tissue from the same patient. In this manner any abnormal findings will be validated. Marker measurements will then be performed in individuals who have had a superficial tumor resected and are being followed for disease recurrence. Any detectable abnormalities at the time when no clinical disease is identifiable will be correlated with the risk of recurrence and marker findings at the time of recurrence.
| Anderson, Jon P; Daifuku, Richard; Loeb, Lawrence A (2004) Viral error catastrophe by mutagenic nucleosides. Annu Rev Microbiol 58:183-205 |
