Genetic mapping and DNA sequence-based analysis of deleted regions on chromosome 16 involved in progression of bladder cancer from occult preneoplastic conditions to invasive disease

Histologic and genetic mapping with 30 hypervariable markers mapped to chro mosome 16 were performed on 234 DNA samples of five cystectomy specimens fr om patients with invasive bladder cancer. Allelic losses of individual mark ers were related to microscopically identified precursor conditions in the entire bladder mucosa and invasive cancer. Their significance for the devel opment and progression of neoplasia from in situ preneoplastic conditions t o invasive disease was analysed by the nearest neighbor algorithm and binom ial maximum likelihood analysis. Using this approach we identified five dis tinct regions of allelic losses defined by their flanking markers and predi cted size as follows. p13.3(D16S418-D16S406, 1.2 cM), p13.1(D16S748-D16S287 , 12.9 cM), q12 1(D16S409-D16S514, 24.0 cM), q22.1 (D16S496-D16S515, 5.4 cM ), and q24 (D16S507-D16S511, 5.9 cM and D16S402-D16S413, 17.4 cM). The regi ons mapping to p13.1 and q24 were involved in early intraurothelial phases of bladder neoplasia such as mild to moderate dysplasia. On the other hand the deleted region mapping to p13.3 was involved in progression of severe d ysplasia/carcinoma in situ to invasive bladder cancer. Testing of markers t hat exhibited statistically significant LOH in relation to progression of n eoplasia from precursor conditions to invasive cancer on 28 tumors and void ed urine samples from 25 patients with bladder cancer revealed that q12.1 s howed LOH in 46.4% of tumor and 32.0% of voided urine samples. The LOH of a single marker D16S541 could be detected in approximately 28% of tumors and 20% of voided urine samples of patients with bladder cancer. These data im ply that the deleted region centered around marker D16S541 spanning approxi mately 10 cM and flanked by D16S409 and D16S415 contains a novel putative t umor suppressor gene or genes playing an important role in the development of human bladder cancer. To facilitate more precise positional mapping and identification of pathogenetically relevent genes, we analysed of human gen ome contig and sequence databases spanning the deleted regions. Multiple kn own candidate genes and several smaller gene-rich areas mapping to the targ et regions of chromosome 16 were identified Oncogene (2001) 20, 5005-5014.