title: NBN gain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer.
abstract: Despite the use of clinical prognostic factors (PSA, T-category and Gleason score), 20-60% of localized prostate cancers (PCa) fail primary local treatment. Herein, we determined the prognostic importance of main sensors of the DNA damage response (DDR): MRE11A, RAD50, NBN, ATM, ATR and PRKDC. We studied copy number alterations in DDR genes in localized PCa treated with image-guided radiotherapy (IGRT; n=139) versus radical prostatectomy (RadP; n=154). In both cohorts, NBN gains were the most frequent genomic alteration (14.4 and 11% of cases, respectively), and were associated with overall tumour genomic instability (p<0.0001). NBN gains were the only significant predictor of 5yrs biochemical relapse-free rate (bRFR) following IGRT (46% versus 77%; p=0.00067). On multivariate analysis, NBN gain remained a significant independent predictor of bRFR after adjusting for known clinical prognostic variables (HR=3.28, 95% CI 1.56-6.89, Wald p-value=0.0017). No DDR-sensing gene was prognostic in the RadP cohort. In vitro studies correlated NBN gene overexpression with PCa cells radioresistance. In conclusion, NBN gain predicts for decreased bRFR in IGRT, but not in RadP patients. If validated independently, Nibrin gains may be the first PCa predictive biomarker to facilitate local treatment decisions using precision medicine approaches with surgery or radiotherapy.
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada. Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Alejandro
authors.initials: A
authors.lastname: Berlin
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada. Informatics and Bio-Computing, Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: Emilie
authors.initials: E
authors.lastname: Lalonde
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Jenna
authors.initials: J
authors.lastname: Sykes
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Gaetano
authors.initials: G
authors.lastname: Zafarana
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada. Informatics and Bio-Computing, Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: Kenneth C
authors.initials: KC
authors.lastname: Chu
authors.affiliation: Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Varune R
authors.initials: VR
authors.lastname: Ramnarine
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada. Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Adrian
authors.initials: A
authors.lastname: Ishkanian
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Dorota H S
authors.initials: DH
authors.lastname: Sendorek
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Ivan
authors.initials: I
authors.lastname: Pasic
authors.affiliation: Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada. Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada.
authors.forename: Wan L
authors.initials: WL
authors.lastname: Lam
authors.affiliation: The Techna Institute, University Health Network, Toronto, ON, Canada.
authors.forename: Igor
authors.initials: I
authors.lastname: Jurisica
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada.
authors.forename: Theo
authors.initials: T
authors.lastname: van der Kwast
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada. Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Michael
authors.initials: M
authors.lastname: Milosevic
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada. Informatics and Bio-Computing, Ontario Institute for Cancer Research, Toronto, ON, Canada.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Boutros
authors.affiliation: Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada. Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
authors.forename: Robert G
authors.initials: RG
authors.lastname: Bristow
mesh_terms: D014408:Biomarkers, Tumor / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D055028:Comparative Genomic Hybridization; D004249:DNA Damage / Q000235:genetics; D018572:Disease-Free Survival; D042822:Genomic Instability; D006801:Humans; D008297:Male; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics* / Q000378:metabolism; D057285:Precision Medicine / Q000379:methods; D011237:Predictive Value of Tests; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000532:radiotherapy* / Q000601:surgery; D011836:Radiation Tolerance / Q000235:genetics; D061089:Radiotherapy, Image-Guided / Q000009:adverse effects / Q000379:methods; D016896:Treatment Outcome
chemical_list: D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins