NKX3.1 haploinsufficiency is prognostic for prostate cancer relapse following surgery or image-guided radiotherapy

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, Robert G. Bristow

Research output: Contribution to journalArticle

36 Scopus citations

Abstract

Background: Despite 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. Methods: Using 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. Results: A 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. Conclusions: Our results support the use of genomic predictors, such as NKX3.1 status, in needle biopsies for personalized approaches to prostate cancer management.

Original languageEnglish (US)
Pages (from-to)308-316
Number of pages9
JournalClinical Cancer Research
Volume18
Issue number1
DOIs
StatePublished - Jan 1 2012

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Locke, J. A., Zafarana, G., Ishkanian, A. S., Milosevic, M., Thoms, J., Have, C. L., Malloff, C. A., Lam, W. L., Squire, J. A., Pintilie, M., Sykes, J., Ramnarine, V. R., Meng, A., Ahmed, O., Jurisica, I., Van Der Kwast, T., & Bristow, R. G. (2012). NKX3.1 haploinsufficiency is prognostic for prostate cancer relapse following surgery or image-guided radiotherapy. Clinical Cancer Research, 18(1), 308-316. https://doi.org/10.1158/1078-0432.CCR-11-2147