We are pursuing a unique strategy to identify early events in bladder cancer development by the genome-wide analysis of somatic changes in tissues from resected bladders and characterized pathologically as urothelial carcinoma. We then extend this analysis into precursor intraurothelial lesions and normal tissue. Here we report on the construction of a high resolution whole-organ histologic and genetic map of bladder cancer development that tracks its progression from in situ precursor conditions to invasive clinically aggressive cancer using total genome and exome sequencing and complemented with HumanOmni 2.5-8 v1 SNP-based Illumina genotyping, combined with CpG island methylation and cDNA microarray platforms derived from 12 whole-organ cystectomy specimens with invasive urothelial carcinoma. This approach provided a high resolution integrated map of structural genome, epigenome, and transcriptome alterations that parallel the development of bladder cancer from early field effects to invasive disease. By analyzing genome-wide patterns of structural genomic, epigenomic, and transcriptome changes, we found three major waves of alterations associated with growth advantage of successive clones reflecting a stepwise conversion of normal urothelial cells into cancer cells. This approach is significant for the identification of specific chromosomal regions as well as epigenetically and transcriptionally modified gene ontologies involved in early clonal expansion of intraurothelial neoplasia and their clonal evolution to carcinoma in situ progressing to invasive cancer. These studies suggest involvement of specific gene networks in early clonal expansion of intraurothelial neoplasia antecedent to microscopically recognizable precursor lesions such as dysplasia and carcinoma in situ. This map represents a prerequisite for specific studies on the mechanisms of incipient phases of bladder cancer development and should have a significant impact on the understanding of human carcinogenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5066. doi:1538-7445.AM2012-5066