Abstract 4601: Punctuated evolution of prostate cancer genomes.

The analysis of exonic DNA from prostate cancers has identified recurrently mutated genes, but the spectrum of alterations across the entire genome has not been profiled extensively in this disease. We sequenced the genomes of 55 primary prostate tumors and matched normal tissues to catalogue somatic alterations and to study how they accumulate during oncogenesis and progression. By implementing an algorithm to identify genomic alterations that arise together, we found abundant sets of DNA rearrangements and deletions that may occur simultaneously in a single cell. This phenomenon, which we term “chromoplexy, frequently accounts for the dysregulation of prostate cancer genes including PTEN, NKX3-1, TP53 and CDKN1B. The somatic fusion of TMPRSS2 and ERG, which occurs in approximately half of prostate cancers, predominantly arises with additional genomic rearrangements in the context of chromoplexy. We further demonstrate that TMPRSS2-ERG fusion-positive tumors display a unique profile of chromoplexy, with complex chains of rearrangements that may fuse DNA from four or more distinct chromosomes. In prostate cancer and other neoplasms, chromoplexy induces considerable genomic derangement in a series of relatively few events. In several instances, multiple cancer genes from non-contiguous regions of the genome appear to be disrupted simultaneously by this process, suggesting a model of punctuated progression during cancer evolution. By characterizing the clonal hierarchy of genomic lesions in prostate tumors, we constructed a path of oncogenic events along which chromoplexy drives prostate carcinogenesis. Citation Format: Sylvan C. Baca, Davide Prandi, Michael S. Lawrence, Juan Miguel Mosquera, Alessandro Romanel, Yotam Drier, Kyung Park, Naoki Kitabayashi, Theresa Y. MacDonald, Eliezer Van Allen, Gregory V. Kryukov, Jean-Philippe Theurillat, T. David Soong, Elizabeth Nickerson, Daniel Auclair, Ashutosh Tewari, Himisha Beltran, Robert C. Onofrio, Gunther Boysen, Candace Guiducci, Christopher E. Barbieri, Kristian Cibulskis, Andrey Sivachenko, Scott L. Carter, Douglas Voet, Gordon Saksena, Michelle R. Cipicchio, Kristin Ardlie, Philip W. Kantoff, Michael F. Berger, Stacey B. Gabriel, Todd R. Golub, Matthew Meyerson, Eric S. Lander, Olivier Elemento, Gad Getz, Francesca Demichelis, Mark A. Rubin, Levi A. Garraway. Punctuated evolution of prostate cancer genomes. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4601. doi:10.1158/1538-7445.AM2013-4601