title: NKX3.1 haploinsufficiency is prognostic for prostate cancer relapse following surgery or image-guided radiotherapy.
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.
authors: Department of Radiation Oncology, Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada.
authors: Jennifer A
authors: JA
authors: Locke
authors: Gaetano
authors: G
authors: Zafarana
authors: Adrian S
authors: AS
authors: Ishkanian
authors: Michael
authors: M
authors: Milosevic
authors: John
authors: J
authors: Thoms
authors: Cherry L
authors: CL
authors: Have
authors: Chad A
authors: CA
authors: Malloff
authors: Wan L
authors: WL
authors: Lam
authors: Jeremy A
authors: JA
authors: Squire
authors: Melania
authors: M
authors: Pintilie
authors: Jenna
authors: J
authors: Sykes
authors: Varune Rohan
authors: VR
authors: Ramnarine
authors: Alice
authors: A
authors: Meng
authors: Omer
authors: O
authors: Ahmed
authors: Igor
authors: I
authors: Jurisica
authors: Theo
authors: T
authors: van der Kwast
authors: Robert G
authors: RG
authors: Bristow
mesh_terms: D015153:Blotting, Western; D003131:Combined Modality Therapy; D055028:Comparative Genomic Hybridization; D005500:Follow-Up Studies; D057895:Haploinsufficiency; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000175:diagnosis* / Q000235:genetics / Q000628:therapy; D011379:Prognosis; D011446:Prospective Studies; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000628:therapy*; D011836:Radiation Tolerance / Q000235:genetics; D061089:Radiotherapy, Image-Guided; D015996:Survival Rate; D014157:Transcription Factors / Q000235:genetics*; D014407:Tumor Cells, Cultured
chemical_list: D018398:Homeodomain Proteins; C491178:NKX3-1 protein, human; D014157:Transcription Factors