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Updated: Dec 25, 2025
miRNA Expression Analyses in Prostate Cancer Clinical Tissues
Published on: September 8, 2015
An Emerging Landscape for Canonical and Actionable Molecular Alterations in Primary and Metastatic Prostate Cancer
Nancy A Dawson1, Matthew Zibelman2, Timothy Lindsay2
1Georgetown-Lombardi Comprehensive Cancer Center, Washington, DC. nancy.a.dawson@gunet.georgetown.edu.
Abstract:
Patients with prostate cancer with tumors harboring defects in DNA-repair genes (DRD) generally do not respond well to AR-directed therapy. Furthermore, canonical pathways evolve during disease progression and may affect treatment with existing therapies. Due to the limited treatment options after failure of hormonal and taxane therapy, and the tumor heterogeneity induced by DRD, we sought to characterize the alterations in primary and metastatic prostate cancer. Tumors from 1,027 patients with advanced prostate cancer that underwent comprehensive genomic profiling for routine clinical care were reviewed to assess DRD mutation rates (27-gene panel) and co-occurring mutations in select canonical prostate cancer pathways. DRD alterations were identified in 20 genes and in 17% of patients (BRCA2 and ATM most common) occurring with slightly higher frequency in specimens from metastatic biopsy sites and men older than 50 years of age. Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred with 3% frequency in the overall cohort but were not enriched in metastatic disease. Biomarkers previously associated with antitumor immunity are found at high frequencies in MSI-H patients, including JAK1 (68%) and PTEN (32%). Lastly, mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were all significantly enriched in metastatic samples. We identified clinically significant subgroups of patients demonstrating (1) defects in DNA-repair pathways, (2) intrinsic prostate cancer signaling pathways that may prevent antitumor immunity, and (3) distinct genomic differences between localized and metastatic prostate cancer. These results lend support that genomic profiling for advanced prostate cancer may identify actionable targets not routinely used in the current metastatic paradigm.
Insights
Advanced prostate cancer patients with DNA-repair gene defects (DRD) show limited response to therapy. Genomic profiling reveals distinct alterations in primary versus metastatic tumors, identifying potential new therapeutic targets.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Patients with prostate cancer and DNA-repair gene defects (DRD) often exhibit poor response to androgen receptor (AR)-directed therapy.
- Tumor heterogeneity and evolving pathways in advanced prostate cancer limit treatment options, especially after hormonal and taxane therapy failure.
Purpose of the Study:
- To characterize genomic alterations in primary and metastatic prostate cancer, focusing on DNA-repair defects and associated pathway mutations.
- To identify distinct genomic profiles between localized and metastatic prostate cancer to inform treatment strategies.
Main Methods:
- Comprehensive genomic profiling of 1,027 advanced prostate cancer patients using a 27-gene panel.
- Analysis of mutation rates in DNA-repair genes and co-occurring mutations in canonical prostate cancer pathways.
- Comparison of genomic alterations between primary and metastatic tumor specimens.
Main Results:
- DNA-repair defects (DRD) were found in 17% of patients across 20 genes (BRCA2, ATM most common), with higher prevalence in metastatic sites and older men.
- Microsatellite instability-high (MSI-H) and tumor mutational burden-high occurred in 3% of patients, without enrichment in metastatic disease.
- Mutations in TP53, AR, PTEN, APC, CTNNB1, and PIK3CA were significantly enriched in metastatic samples; MSI-H patients showed high frequencies of JAK1 and PTEN.
Conclusions:
- Genomic profiling identifies distinct patient subgroups with DNA-repair defects, immune-evading pathways, and differences between localized and metastatic disease.
- Genomic profiling of advanced prostate cancer can reveal actionable targets beyond the current metastatic treatment paradigm.
- Understanding tumor heterogeneity and specific genomic alterations is crucial for developing effective therapies for advanced prostate cancer.
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