Departments of Radiation Oncology, Medical Biophysics, Laboratory Medicine and Pathology and Biostatistics, University of Toronto, Ontario Cancer Institute/Princess Margaret Hospital-University Health Network.
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. This data was 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.
Written by:
Locke JA, Zafarana G, Ishkanian AS, Milosevic M, Thoms J, Have CL, Malloff CA, Lam WL, Squire JA, Pintilie M, Sykes J, Ramnarine VR, Meng AX, Ahmed O, Jurisica I, van der Kwast T, Bristow RG. Are you the author?
Reference: Clin Cancer Res. 2011 Nov 10. [Epub ahead of print].
PubMed Abstract
PMID: 22048240
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