Genomic Landscape of Bladder Cancer Development from Incipient Field Effects to Invasive Disease
Tadeusz Majewski, Jolanta Bondaruk, Woonyoung Choi, Sangkyou Lee, Woonbok Chung, Keith Baggerly, Colin Dinney, H Barton Grossman, Jean-Pierre Issa, David McConkey, Steve Scherer, Bogdan Czerniak. UT MD Anderson Cancer Center, Houston, TX; Texas Human Genome Sequencing Center, Baylor College of Medicine, Houston, TX; Temple University School of Medicine, Philadelphia, PA
Background: We are pursuing a unique strategy to identify early events in bladder cancer development by the analysis of somatic changes in tissues from resected bladder and characterized pathologically as transitional cell carcinoma and then extending this analysis outward into precursor intraurothelial lesions and normal tissue.
Design: We used the whole-organ histologic and genetic mapping strategy coupled with next generation whole exome sequencing using a combination of NimbleGen whole exome capture with Illumina HiSeq 2000 exome sequencing (20x coverage) complemented with custom genotyping using Illumina HumanOmni2.5_8 chips and whole genome methylation analyses to define the molecular alterations that were associated with the progression of muscle-invasive bladder cancer in one surgical specimen.
Results: We identified a total of 18 structurally significant mutations, three of which appeared to be clear “driver” mutations that had been annotated previously. Alterations in chromatin hyper- and hypomethylation predominated in all of the regions that contained normal-appearing urothelium or low-grade dysplasia. In total, 31 genes were hypermethylated and 26 genes were hypomethylated. Copy number alterations were numerous (n=242) in areas that contained high-grade dysplasia suggesting that genomic instability preceded the emergence of driver mutations in what ultimately emerged as the dominant tumor subclone. Chromosomal gains (n=216) vastly outnumbered losses (n=26) suggesting that genomic instability was not a random process. Finally, genomic instability increased dramatically at the transition from high-grade dysplasia to TCC.
Conclusions: Our study has important implications for understanding the “field effect” that underlies bladder cancer carcinogenesis and progression. The data strongly suggest that epigenetic (methylation-based) alterations targeting DNA repair, developmental signaling, and invasion/migration were present at the earliest stages throughout the urothelium and were most likely responsible for the genomic instability and proliferation that lays the foundation for progression to high-grade dysplasia.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 5, 2013 9:30 AM
Poster Session III # 228, Tuesday Morning