• Jennifer A Locke, Gaetano Zafarana, Adrian S Ishkanian, Michael Milosevic, John Thoms, Cherry L Have, Chad A Malloff, Wan L Lam, Jeremy A Squire, Melania Pintilie, Jenna Sykes, Varune Rohan Ramnarine, Alice Meng, Omer Ahmed, Igor Jurisica, Theo van der Kwast, and Robert G Bristow.
• Department of Radiation Oncology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
• Clin Cancer Res. 2012 Jan 1; 18 (1): 308-16.

BackgroundDespite the use of prostate specific antigen (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 toward 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 cooperation with c-MYC during prostate cancer progression.MethodsUsing high-resolution array comparative genomic hybridization (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) by the Kaplan-Meier method and Cox proportional hazards models.ResultsA screen of the aCGH-IGRT data for TIC genes showed frequent copy number alterations for NKX3.1, 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 with a public aCGH database. NKX3.1 status was associated with positive biopsies post-IGRT and increased clonogen radioresistance in vitro.ConclusionsOur results support the use of genomic predictors, such as NKX3.1 status, in needle biopsies for personalized approaches to prostate cancer management.© 2011 AACR.

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