title: DOC-2/DAB2 interacting protein status in high-risk prostate cancer correlates with outcome for patients treated with radiation therapy.
abstract: OBJECTIVE
  This pilot study investigates the role of DOC-2/DAB2 Interacting Protein (DAB2IP) and enhancer of zeste homolog 2 (EZH2) as prognostic biomarkers in high-risk prostate cancer patients receiving definitive radiation therapy.
  
  
  METHODS
  Immunohistochemistry was performed and scored by an expert genitourinary pathologist. Clinical endpoints evaluated were freedom from biochemical failure (FFBF), castration resistance-free survival (CRFS), and distant metastasis-free survival (DMFS). Log-rank test and Cox regression were used to determine significance of biomarker levels with clinical outcome.
  
  
  RESULTS
  Fifty-four patients with high-risk prostate cancer (stage ≥ T3a, or Gleason score ≥ 8, or prostate-specific antigen level ≥ 20 ng/mL) treated with radiation therapy from 2005 to 2012 at our institution were evaluated. Nearly all patients expressed EZH2 (98%), whereas 28% of patients revealed DAB2IP reduction and 72% retained DAB2IP. Median follow-up was 34.0 months for DAB2IP-reduced patients, 29.9 months for DAB2IP-retained patients, and 32.6 months in the EZH2 study. Reduction in DAB2IP portended worse outcome compared with DAB2IP-retained patients, including FFBF (4-year: 37% vs 89%, P=.04), CRFS (4-year: 50% vs 90%, P=.02), and DMFS (4-year: 36% vs 97%, P=.05). Stratified EZH2 expression trended toward significance for worse FFBF and CRFS (P=.07). Patients with reduced DAB2IP or highest-intensity EZH2 expression exhibited worse FFBF (4-year: 32% vs 95%, P=.02), CRFS (4-year: 28% vs 100%, P<.01), and DMFS (4-year: 39% vs 100%, P=.04) compared with the control group.
  
  
  CONCLUSIONS
  Loss of DAB2IP is a potent biomarker that portends worse outcome despite definitive radiation therapy for patients with high-risk prostate cancer. Enhancer of zeste homolog 2 is expressed in most high-risk tumors and is a less potent discriminator of outcome in this study. The DAB2IP status in combination with degree of EZH2 expression may be useful for determining patients with worse outcome within the high-risk prostate cancer population.
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Corbin
authors.initials: C
authors.lastname: Jacobs
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Vasu
authors.initials: V
authors.lastname: Tumati
authors.affiliation: Department of Pathology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Payal
authors.initials: P
authors.lastname: Kapur
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jingsheng
authors.initials: J
authors.lastname: Yan
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Hong
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Manzerul
authors.initials: M
authors.lastname: Bhuiyan
authors.affiliation: Department of Clinical Sciences, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Xian-Jin
authors.initials: XJ
authors.lastname: Xie
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center, Dallas, Texas.
authors.forename: David
authors.initials: D
authors.lastname: Pistenmaa
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Lan
authors.initials: L
authors.lastname: Yu
authors.affiliation: Simmons Cancer Center, Dallas, Texas; Department of Urology, University of Texas Southwestern Medical Center, Dallas, Texas.
authors.forename: Jer-Tsong
authors.initials: JT
authors.lastname: Hsieh
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center, Dallas, Texas.
authors.forename: Debabrata
authors.initials: D
authors.lastname: Saha
authors.affiliation: Department of Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, Texas; Simmons Cancer Center, Dallas, Texas. Electronic address: Nathan.Kim@utsouthwestern.edu.
authors.forename: D W Nathan
authors.initials: DW
authors.lastname: Kim
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D014408:Biomarkers, Tumor / Q000378:metabolism*; D002135:Calcium-Binding Proteins / Q000378:metabolism*; D018572:Disease-Free Survival; D000071221:Enhancer of Zeste Homolog 2 Protein; D005500:Follow-Up Studies; D006801:Humans; D016014:Linear Models; D008297:Male; D008875:Middle Aged; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D010865:Pilot Projects; D063151:Polycomb Repressive Complex 2 / Q000097:blood*; D011379:Prognosis; D016016:Proportional Hazards Models; D011467:Prostate / Q000378:metabolism; D017430:Prostate-Specific Antigen / Q000097:blood; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D064129:Prostatic Neoplasms, Castration-Resistant / Q000378:metabolism / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy; D013739:Testosterone / Q000097:blood; D016896:Treatment Outcome; D020703:ras GTPase-Activating Proteins / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D002135:Calcium-Binding Proteins; C462952:DAB2IP protein, human; C091524:DOC2A protein, human; D009419:Nerve Tissue Proteins; D020703:ras GTPase-Activating Proteins; D013739:Testosterone; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D017430:Prostate-Specific Antigen