Genetic modeling of human urinary bladder carcinogenesis

We developed a model of human urinary bladder cancer progression from in si tu precursor lesions to invasive carcinoma using whole organ histologic and genetic mapping. The model represents a high-density and detailed analysis regarding allelic losses on chromosomes 4, 8, 9, 11, and 17 as revealed by testing of 234 samples obtained From five cystectomy specimens. The sample s corresponded to microscopically identified intraurothelial precursor cond itions ranging from dysplasia to carcinoma in situ and invasive cancer. The initial analysis of paired normal and tumor DNA samples disclosed allelic losses in 72 of 225 tested hypervariable DNA markers. Subsequent use of the se markers on all mucosal samples revealed that 47 had alterations with a s tatistically significant relation to urothelial neoplasia. The allelic loss es clustered in 33 distinct chromosomal regions, indicating the location of putative tumor suppressor genes involved in the development and progressio n of urinary bladder cancer. Some of the markers with statistically signifi cant allelic losses mapped to the regions containing well-characterized tum or suppressor genes but many were located in previously unknown loci. The m ajority of statistically significant allelic losses (70%) occurred early in low-grade intraurothelial dysplasia, and some of them involved adjacent ar eas of morphologically normal mucosa preceding the development of microscop ically recognizable precursor lesions. The remaining 30% of markers develop ed allelic losses in the later phases of urothelial neoplasia, implicating their involvement in progression to invasive disease. Markers exhibiting al lelic losses in early phases of urothelial neoplasia could be used for dete ction of occult preclinical or even premicroscopic phases of urinary bladde r cancer, whereas markers that showed allelic losses in the later phases of the process could serve as indicators of progression to invasive disease. The approach used in this study facilitates genome-wide modeling of cancer progression and provides important chromosomal landmarks for more specific studies of multistep urinary bladder carcinogenesis. (C) 2000 Wiley-Liss, I nc.