NBNgain is predictive for adverse outcome following image-guided radiotherapy for localized prostate cancer

// Alejandro Berlin 1,2,* , Emilie Lalonde 1,3,* , Jenna Sykes 1 , Gaetano Zafarana 1 , Kenneth C. Chu 1,3 , Varune R. Ramnarine 4 , Adrian Ishkanian 1,2 , Dorota H.S. Sendorek 1 , Ivan Pasic 1 , Wan L. Lam 4,5 , Igor Jurisica 6 , Theo van der Kwast 1 , Michael Milosevic 1,2 , Paul C. Boutros 1,3 and Robert G. Bristow 1,2 1 Departments of Radiation Oncology, Medical Biophysics, Medical Oncology, Laboratory Medicine and Pathology, Pharmacology & Toxicology and Biostatistics, Computer Science, University of Toronto, Toronto, ON, Canada 2 Radiation Medicine Program, Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada 3 Informatics and Bio-Computing, Ontario Institute for Cancer Research, Toronto, ON, Canada 4 Vancouver Prostate Centre & Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada 5 Department of Integrative Oncology, British Columbia Cancer Research Centre, Vancouver, BC, Canada 6 The Techna Institute, University Health Network, Toronto, ON, Canada * These authors contributed equally to this work Correspondence: Robert G. Bristow, email: // Keywords : prostate cancer, NBN, MRN complex, radiotherapy, biomarker, aCGH Received : July 10, 2014 Accepted : August 26, 2014 Published : August 27, 2014 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.