ALTERATIONS IN PHENOTYPIC BIOCHEMICAL MARKERS IN BLADDER EPITHELIUM DURING TUMORIGENESIS

Phenotypic biochemic-al markers of oncogenesis and differentiation wer e mapped in bladder biopsies to investigate changes that occur in blad der tumorigenesis and to identify markers for increased bladder cancer risk. Touch preparations from biopsy specimens from 30 patients were obtained from tumors, the adjacent bladder epithelium, and random dist ant bladder epithelium. Markers, including DNA ploidy, epidermal growt h factor receptor (EGFR), and oncoproteins, were quantified in individ ual cells by using quantitative fluorescence image analysis. Cluster a nalysis revealed the markers fell into three independent groups: (i) G -actin and EGFR; (ii) ploidy, cytology, and p185 (HER-2/neu oncoprotei n) (ERBB2); and (iii) p300, a low-grade tumor antigen. Each marker dis played a gradient of abnormality from distant field to adjacent rield to tumor. Different patterns for each marker suggested a developmental sequence of bladder cancer oncogenesis; G-actin was altered in 58% of distant biopsies (vs. 0/6 normats, P < 0.001), ploidy and cytology we re altered in <20% of distant fields and almost-equal-to 80% of tumors , and the other markers were intermediate. Patterns of EGFR and pl85 s uggest low-and high-grade tracks diverge early (P < 0.05 by Mann-Whitn ey U test for EGFR and ANOVA for p185). In conclusion, this study show s that a sequence of phenotypic changes accompanies development and pr ogression of bladder cancers. Biochemical alterations in cells of the bladder field are often detectable before abnormal pathology, and mark ers previously thought to be limited to tumors were found in the field . The hierarchy of expression may be useful in identifying high-risk p atients, assessing completeness of response to therapy, and monitoring and predicting recurrence.