Genomic Landscape of Bladder Cancer Development from Incipient Field Effects to Invasive Disease
Tadeusz Majewski, Jolanta Bondaruk, Shizhen Zhang, Sangkyou Lee, Keith Baggerly, Colin Dinney, Herbert Barton Grossman, Xifeng F Wu, Jean-Pierre Issa, Wei Zhang, Richard Gibbs, Steven E Scherer, Bogdan A Czerniak. UT MD Anderson Cancer Center, Houston, TX; Fels Institute for Cancer Research and Molecular Biology, Philadelphia, PA; Baylor College of Medicine, Houston, TX
Background: 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 transitional cell carcinoma. We then extend this analysis into precursor intraurothelial lesions and normal urothelium in the context of the entire organ descriptively referred to as whole-organ histologic and genetic mapping.
Design: Data was derived from 12 tumor-peripheral blood normal pairs to identify somatic variants using NimbleGen whole exome capture with Illumina HiSeq 2000 exome sequencing (20x coverage) and whole genome sequencing (4x coverage) complemented with custom genotyping using Illumina HumanOmni2.5_8 chips. All somatic mutations were tested geographically across the bladder using semi-automated PCR-based sequencing to generate whole-organ maps of bladder cancer development from in situ field effects. These results are being augmented by epigenomic and transcriptome analyses using Illumina chips.
Results: Variant analysis, after filtering, revealed that more than 70% of the somatic changes present across the samples were classified as novel and included nearly 4000 missense and approximately 100 nonsense mutations as well as several frame shift alterations. Preliminary analysis revealed mutations in the RAS-ERK MAPK signaling pathway in the early in situ phase of bladder carcinogenesis and the involvement of the p53 gene network in the progression from carcinoma in situ to invasive cancer.
Conclusions: Genome variant analysis in the entire bladder mucosa revealed complex genomic alterations engaged in the development of diffused mucosal field effects with predominant involvement of the Ras-ERK related genes. The hallmark of the secondary clonal evolution into carcinoma in situ progressing to invasive disease was the alterations of the p53 gene network.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 20, 2012 9:30 AM
Poster Session III # 266, Tuesday Morning