Background: Despite the use of PSA, Gleason-score, and T-category as prognostic factors, up to 40% of patients with intermediate-risk prostate cancer will fail radical prostatectomy or precision image-guided radiotherapy (IGRT). Additional genetic prognosticators are needed to triage these patients towards intensified combination therapy with novel targeted therapeutics. We tested the role of the NKX3.1 gene as a determinant of treatment outcome given its reported roles in tumor initiating cell (TIC) renewal, the DNA damage response and co-operation with c-MYC during prostate cancer progression. Methods: Using high-resolution aCGH, we profiled the copy number alterations in TIC genes using tumor DNA from frozen needle biopsies derived from 126 intermediate-risk patients who underwent IGRT. These data were correlated to biochemical relapse-free rate (bRFR) using the Kaplan-Meier method and Cox proportional hazards models. Results: A screen of the aCGH-IGRT data for TIC genes showed frequent copy number alterations forNKX3.1, PSCA and c-MYC. NKX3.1 haploinsufficiency was associated with increased genomic instability independent of PSA, T-category and Gleason-score. After adjusting for clinical factors in a multivariate model, NKX3.1 haploinsufficiency was associated with bRFR when tested alone (HR=3.05, 95% CI:1.46-6.39, p=0.0030) or when combined with c-MYC gain (HR=3.88, 95% CI:1.78-8.49, p=0.00067). A similar association was observed for patients following radical prostatectomy using a public aCGH database. NKX3.1 status was associated with positive biopsies post-IGRT and increased clonogen radioresistance, in vitro. Conclusions: Our results support the use of genomic predictors, such as NKX3.1 status, in needle biopsies, for personalized approaches to prostate cancer management.
- Received August 22, 2011.
- Revision received October 18, 2011.
- Accepted October 24, 2011.
- Copyright © 2011, American Association for Cancer Research.