NBN gain is predictive for adverse outcome following imageguided radiotherapy for localized prostate cancer

Alejandro Berlin, Emilie Lalonde, Jenna Sykes, Gaetano Zafarana, Kenneth C. Chu, Varune R. Ramnarine, Adrian Ishkanian, Dorota H S Sendorek, Ivan Pasic, Wan L. Lam, Igor Jurisica, Theo van der Kwast, Michael Milosevic, Paul C. Boutros, Robert G. Bristow

Research output: Contribution to journalArticle

20 Citations (Scopus)

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 relapsefree 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.

Original languageEnglish (US)
Pages (from-to)11081-11090
Number of pages10
JournalOncotarget
Volume5
Issue number22
StatePublished - 2014
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Radiotherapy
DNA Damage
Image-Guided Radiotherapy
Genes
Precision Medicine
Neoplasm Grading
Genomic Instability
Tumor Biomarkers
Prostatectomy
Multivariate Analysis
Therapeutics
Neoplasms

Keywords

  • aCGH
  • Biomarker
  • MRN complex
  • NBN
  • Prostate cancer
  • Radiotherapy

ASJC Scopus subject areas

  • Oncology

Cite this

Berlin, A., Lalonde, E., Sykes, J., Zafarana, G., Chu, K. C., Ramnarine, V. R., ... Bristow, R. G. (2014). NBN gain is predictive for adverse outcome following imageguided radiotherapy for localized prostate cancer. Oncotarget, 5(22), 11081-11090.

NBN gain is predictive for adverse outcome following imageguided radiotherapy for localized prostate cancer. / Berlin, Alejandro; Lalonde, Emilie; Sykes, Jenna; Zafarana, Gaetano; Chu, Kenneth C.; Ramnarine, Varune R.; Ishkanian, Adrian; Sendorek, Dorota H S; Pasic, Ivan; Lam, Wan L.; Jurisica, Igor; van der Kwast, Theo; Milosevic, Michael; Boutros, Paul C.; Bristow, Robert G.

In: Oncotarget, Vol. 5, No. 22, 2014, p. 11081-11090.

Research output: Contribution to journalArticle

Berlin, A, Lalonde, E, Sykes, J, Zafarana, G, Chu, KC, Ramnarine, VR, Ishkanian, A, Sendorek, DHS, Pasic, I, Lam, WL, Jurisica, I, van der Kwast, T, Milosevic, M, Boutros, PC & Bristow, RG 2014, 'NBN gain is predictive for adverse outcome following imageguided radiotherapy for localized prostate cancer', Oncotarget, vol. 5, no. 22, pp. 11081-11090.
Berlin A, Lalonde E, Sykes J, Zafarana G, Chu KC, Ramnarine VR et al. NBN gain is predictive for adverse outcome following imageguided radiotherapy for localized prostate cancer. Oncotarget. 2014;5(22):11081-11090.
Berlin, Alejandro ; Lalonde, Emilie ; Sykes, Jenna ; Zafarana, Gaetano ; Chu, Kenneth C. ; Ramnarine, Varune R. ; Ishkanian, Adrian ; Sendorek, Dorota H S ; Pasic, Ivan ; Lam, Wan L. ; Jurisica, Igor ; van der Kwast, Theo ; Milosevic, Michael ; Boutros, Paul C. ; Bristow, Robert G. / NBN gain is predictive for adverse outcome following imageguided radiotherapy for localized prostate cancer. In: Oncotarget. 2014 ; Vol. 5, No. 22. pp. 11081-11090.
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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 relapsefree 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.",
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T1 - NBN gain is predictive for adverse outcome following imageguided radiotherapy for localized prostate cancer

AU - Berlin, Alejandro

AU - Lalonde, Emilie

AU - Sykes, Jenna

AU - Zafarana, Gaetano

AU - Chu, Kenneth C.

AU - Ramnarine, Varune R.

AU - Ishkanian, Adrian

AU - Sendorek, Dorota H S

AU - Pasic, Ivan

AU - Lam, Wan L.

AU - Jurisica, Igor

AU - van der Kwast, Theo

AU - Milosevic, Michael

AU - Boutros, Paul C.

AU - Bristow, Robert G.

PY - 2014

Y1 - 2014

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AB - 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 relapsefree 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.

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KW - Radiotherapy

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