Abstract 3181: The genomic evolution of prostate cancer under the selective pressure of anti-androgen therapy.

Abstract

Abstract Background: The implementation of novel technologies such as array comparative genomic hybridization (aCGH) and next-generation sequencing has led to a deeper understanding of the genomic nature of cancer. However, these analyses have classically been done without respecting intra-tumor heterogeneity. Here, we applied a methodology that allows us analyzing the genomic profile of distinct tumor populations from individual tumors and their clonal evolution during the progression to castration-resistant disease. Methods: Matched pre- and post- hormone treated fresh frozen and/or formalin fixed prostate cancer samples were selected from our biobank. Clonal tumor populations were flow-sorted according to their nuclear DNA content. Sorted tumor populations were subjected to whole genome CGH and to full exome sequencing analyses by the use of Agilent SurePrint 2x400k microarrays and the SureSelect All Exon Kit, respectively. Results: The genomic analyses of the tumor samples underscore the presence of significant intra-tumoral heterogeneity. The analysis of matched tumor specimens allowed us to identify two particular patterns of tumor evolution during the progression after treatment: First, a more parallel pattern of tumor evolution, in which the ancestor population is breeding multiple aneuploid tumor clones. In this case, only the 2N ancestor population is able to withstand therapy by the acquisition of few specific genomic aberrations whereas the aneuploid populations are eradicated. Second, a more sequential pattern of tumor evolution with a tumor population that evolves out of a continuous line of clones. This population shows increasing signs of genomic instability over time, with a punctual event of chromothripsis (a massive destruction and rearrangement of chromosomal structures) resulting in castration-resistant clonal tumor populations. Conclusions: Genomic profiling of distinct clonal tumor populations during prostate cancer progression allows for analysis of intra-tumoral heterogeneity and the underlying clonal evolution. Importantly, this approach identifies genomic aberrations that were selected for under the pressure of hormone ablation therapy. Citation Format: Joël R. Gsponer, Tanja Dietsche, Alexander Rufle, Elisabeth Lenkiewicz, Tobias Zellweger, Alexander Bachmann, Daniel D. Von Hoff, M T. Barrett, Cyrill Rentsch, Christian Ruiz, Lukas Bubendorf. The genomic evolution of prostate cancer under the selective pressure of anti-androgen therapy. [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 3181. doi:10.1158/1538-7445.AM2013-3181