Unknown,Transcriptomics,Genomics,Proteomics

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Comparative analyses of chromosome alterations in metastases in castration-resistant prostate cancer patients

ABSTRACT: 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 CGH, gene expression arrays, and FISH. By cluster 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 over-representation 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. The aim of this study was to characterize the genomic changes identified in a set of matched castrate-resistant primary and metastatic prostate cancers. Tumor cells were isolated by laser-capture microdissection from 14 patients, a total of 54 tumor samples. LCM capture samples were isolated from multiple metastastases from all but one patient from whom a single metastasis was available. Primary prostate tumor samples were collected from 12 patients. DNA was amplified by either ligation-mediated PCR (LMP) or WGA (Sigma-Aldrich, St. Louis, MO, USA). Reference DNA was isolated from peripheral blood from a single female individual.

ORGANISM(S): Homo sapiens

SUBMITTER: Peter Nelson

PROVIDER: E-GEOD-18259 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer.

Holcomb Ilona N IN Young Janet M JM Coleman Ilsa M IM Salari Keyan K Grove Douglas I DI Hsu Li L True Lawrence D LD Roudier Martine P MP Morrissey Colm M CM Higano Celestia S CS Nelson Peter S PS Vessella Robert L RL Trask Barbara J BJ

Cancer research 20090922 19

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 profil ...[more]

PMID: 19773449

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Dataset Information

Comparative analyses of chromosome alterations in metastases in castration-resistant prostate cancer patients

Publications

Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with castration-resistant prostate cancer.

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