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Updated: Jan 25, 2026
Pre-clinical Orthotopic Murine Model of Human Prostate Cancer
Published on: August 29, 2016
Similar incidence of DNA damage response pathway alterations between clinically localized and metastatic prostate
Isaac E Kim1, Sinae Kim2, Arnav Srivastava3
1The Warren Alpert Medical School of Brown University, Providence, RI, USA.
Background:
In this era of precision medicine, the DNA damage response (DDR) pathway has been shown to be a viable target of intervention in metastatic castration-resistant prostate cancer (CRPC) as approximately one-third of CRPC patients harbor DDR pathway mutations. To determine whether DDR pathway is a potential therapeutic target in localized disease, we analyzed The Cancer Genome Atlas (TCGA) in the present study.
Methods:
TCGA is a publically available cancer genome database that is sponsored by the United States National Cancer Institute. Total of 455 cases were available in the database at the time of this analysis.
Results:
DDR pathway gene mutations or copy number alterations were present in 136 (29.9%) of the 455 cases. On a univariate analysis, DDR pathway status did not correlate with serum prostate specific antigen, tumor stage or grade. However, among patients with high-risk features post-operatively (pathologic stage ≥ T3, Gleason score ≥ 8, or PSA > 20 ng/ml), DDR pathway alteration was associated with a lower overall survival (p = 0.0291).
Conclusions:
Collectively these results suggest that DDR pathway alterations may also be significant in localized prostate cancer and agents such as PARP inhibitors should be considered in patients with a high-risk disease.
Insights
DNA damage response (DDR) pathway alterations are common in localized prostate cancer. These alterations correlate with poorer survival in high-risk patients, suggesting DDR-targeted therapies may benefit this group.
Area of Science:
- Oncology
- Genetics
- Precision Medicine
Background:
- The DNA damage response (DDR) pathway is a validated therapeutic target in metastatic castration-resistant prostate cancer (CRPC).
- Approximately one-third of CRPC patients exhibit DDR pathway mutations.
Purpose of the Study:
- To investigate the role of DDR pathway alterations in localized prostate cancer.
- To determine if DDR pathway is a potential therapeutic target in early-stage disease.
Main Methods:
- Analysis of The Cancer Genome Atlas (TCGA) database.
- Inclusion of 455 localized prostate cancer cases.
- Examination of DDR pathway gene mutations and copy number alterations.
Main Results:
- DDR pathway alterations were identified in 29.9% (136/455) of cases.
- No univariate correlation was found between DDR status and standard prognostic factors (PSA, tumor stage, grade).
- DDR pathway alteration was significantly associated with reduced overall survival in high-risk patients (pathologic stage ≥ T3, Gleason score ≥ 8, or PSA > 20 ng/ml).
Conclusions:
- DDR pathway alterations are significant in localized prostate cancer.
- High-risk patients with DDR alterations may benefit from targeted therapies.
- Agents like PARP inhibitors warrant consideration for this patient subgroup.
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