Integrated Genome Sequence, Epigenome, and Transcriptome Map of Bladder Cancer Development from Field Effects.
Tadeusz Majewski, Woonbok Chung, Yun Wu, David E Cogdell, Jolanta Bondaruk, Shizhen Zhang, Sang Kil Lee, Sangkyou Lee, Li Shen, Caimiao Wei, Suk Young Yoo, Woonyoung Choi, David McConkey, John N Weinstein, Keith A Baggerly, Jean-Pierre Issa, Wei Zhang, Steve E Scherer, Bogdan A Czerniak. UT MD Anderson Cancer Center, Houston, TX; Baylor College of Medicine, Houston, TX
Background: Genomic maps that track the development of human cancer from its in situ precursor conditions to invasive disease can facilitate the search for genes and genomic sequences involved in the development of cancer. The identification of those chromosomal regions and their positional target genes as well as non-coding sequences that provide growth advantage for the incipient preneoplastic conditions can provide novel insights on molecular mechanisms of cancer development. Such an approach is also critical for the identification of novel biomarkers as well as targets for preventive and therapeutic strategies.
Design: 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 exome deep sequencing and 1M SNP-based Illumina genotyping combined with CpG island methylation and cDNA microarray technology platforms. This approach provided a high resolution integrated pattern of structural genome, epigenome, and transcriptome alterations that parallel the development of bladder cancer from early field effects to invasive disease.
Results: By analyzing genome-wide patterns of structural genomic (copy loss or gain), 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. In particular, 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 ras/raf gene network in early clonal expansion of intraurothelial neoplasia.
Conclusions: 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.
Category: Special Category - Pan-genomic/Pan-proteomic approaches to Cancer
Tuesday, March 1, 2011 9:15 AM
Platform Session: Section H 1, Tuesday Morning