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Comparative Analyses of Chromosome Alterations in Soft-Tissue Metastases within and across Patients with Castration-Resistant Prostate Cancer

Divisions of ¹ Human Biology and ² Public Health Sciences, Fred Hutchinson Cancer Research Center; Departments of ³ Genetics, ⁴ Urology, and ⁵ Medicine (Division of Oncology), University of Washington; and ⁶ Veterans Affairs Puget Health Sciences Center, Seattle, Washington; and ⁷ Department of Pathology, Stanford University, Stanford, California

Requests for reprints: Barbara J. Trask, Human Biology Division, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Mail Stop C3-168, PO Box 19024, Seattle, WA 98109. Phone: 206-667-1470; Fax: 206-667-4023; E-mail: btrask{at}fhcrc.org.

Key Words: Prostate cancer • castration-resistant metastases • metastatic prostate cancer • array CGH • expression • genomic alterations • TMPRSS2-ERG fusion

Androgen deprivation is the mainstay of therapy for progressive prostate cancer. Despite initial and dramatic tumor inhibition, most men eventually fail therapy and die of metastatic castration-resistant (CR) disease. Here, we characterize the profound degree of genomic alteration found in CR tumors using array comparative genomic hybridization (array CGH), gene expression arrays, and fluorescence in situ hybridization (FISH). Bycluster analysis, we show that the similarity of the genomic profiles from primary and metastatic tumors is driven by the patient. Using data adjusted for this similarity, we identify numerous high-frequency alterations in the CR tumors, such as 8p loss and chromosome 7 and 8q gain. By integrating array CGH and expression array data, we reveal genes whose correlated values suggest they are relevant to prostate cancer biology. We find alterations that are significantly associated with the metastases of specific organ sites, and others with CR tumors versus the tumors of patients with localized prostate cancer not treated with androgen deprivation. Within the high-frequency sites of loss in CR metastases, we find an overrepresentation of genes involved in cellular lipid metabolism, including PTEN. Finally, using FISH, we verify the presence of a gene fusion between TMPRSS2 and ERG suggested by chromosome 21 deletions detected by array CGH. We find the fusion in 54% of our CR tumors, and 81% of the fusion-positive tumors contain cells with multiple copies of the fusion. Our investigation lays the foundation for a better understanding of and possible therapeutic targets for CR disease, the poorly responsive and final stage of prostate cancer. [Cancer Res 2009;69(19):7793–802]