摘要：

Intratumoral clonal heterogeneity and complexity are frequent in prostate cancer and can mask critical cell populations. Aim of this study was to analyze the genomic clonal evolution of a hormone-sensitive prostate adenocarcinoma and its development to hormonal independence over the entire course of disease by using standard pathological as well as high definition genomic profiling technologies. We collected three frozen prostate carcinoma specimens from the same patient over a time period of eight years (2000, 2007, 2008). Using a multistep approach involving high-end flow-sorting based on degree of aneuploidy, distinct clonal populations were isolated and analyzed for genomic aberrations by high-resolution array-CGH using the 244k Agilent microarrays (Agilent Technologies). Relevant genomic aberrations, such as gene amplifications, deletions and translocations, were confirmed by fluorescence in-situ hybridization (FISH) and expression was analyzed by immunohistochemistry. We show the genomic evolution of a clonal population of hormone-sensitive prostate cancer (2000) into two neoplastic (one diploid and one aneuploid) hormone-independent populations after orchiectomy. This process was accompanied by androgen receptor gene amplification, as well as by novel undescribed genomic aberrations. Interestingly, only the aneuploid population, but not the diploid one responded to secondary anti-androgenic therapy in 2007. High resolution genomic profiling of distinct clonal populations of a prostate cancer over time reveals new insights into the clonal evolution of the tumor cells. These genomic aberrations and their protein products may lead to the discovery of novel genomic-driven therapeutic targets against prostate cancer.

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