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Updated: Jun 20, 2026
A Bioluminescent and Fluorescent Orthotopic Syngeneic Murine Model of Androgen-dependent and Castration-resistant Prostate Cancer
Published on: March 6, 2018
Comparative analyses of chromosome alterations in soft-tissue metastases within and across patients with
Ilona N Holcomb1, Janet M Young, Ilsa M Coleman
1Divisions of Human Biology, Fred Hutchinson Cancer Research Center, University of Washington, Seattle, Washington, USA.
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 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.
Insights
Genomic alterations in metastatic castration-resistant prostate cancer include 8p loss and 7/8q gain. A TMPRSS2-ERG gene fusion occurs in over half of these advanced prostate cancers.
Area of Science:
- Oncology
- Genomics
- Prostate Cancer Research
Background:
- Androgen deprivation therapy is standard for progressive prostate cancer.
- Most patients develop resistance, progressing to metastatic castration-resistant (CR) prostate cancer.
- Understanding the genomic landscape of CR prostate cancer is crucial for new therapies.
Purpose of the Study:
- To characterize genomic alterations in metastatic castration-resistant prostate cancer.
- To identify genes and pathways involved in CR prostate cancer progression.
- To investigate the role of specific genomic alterations, including gene fusions, in CR disease.
Main Methods:
- Array comparative genomic hybridization (array CGH) to detect copy number variations.
- Gene expression arrays to analyze gene activity.
- Fluorescence in situ hybridization (FISH) to confirm gene fusions.
- Cluster analysis to assess genomic profile similarity.
Main Results:
- High-frequency genomic alterations in CR tumors include 8p loss and chromosome 7 and 8q gain.
- Specific genomic alterations correlate with organ-specific metastases and CR disease.
- Genes involved in cellular lipid metabolism, including PTEN, are overrepresented at sites of high-frequency loss.
- A TMPRSS2-ERG gene fusion was identified in 54% of CR tumors, with multiple copies in 81% of fusion-positive cases.
Conclusions:
- Genomic profiling reveals significant alterations driving castration-resistant prostate cancer.
- Identified genomic alterations and gene fusions offer potential therapeutic targets.
- This study provides a foundation for understanding and treating advanced prostate cancer.
