TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy: Implications for fusion status anddsb repair

Alan Dal Pra, Emilie Lalonde, Jenna Sykes, Fiona Warde, Adrian Ishkanian, Alice Meng, Chad Maloff, John Srigley, Anthony M. Joshua, Gyorgy Petrovics, Theodorus Van Der Kwast, Andrew Evans, Michael Milosevic, Fred Saad, Colin Collins, Jeremy Squire, Wan Lam, Tarek A. Bismar, Paul C. Boutros, Robert G. Bristow

Research output: Contribution to journalArticle

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Abstract

Background: Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). Methods: Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) < 8, prostate-specific antigen (PSA) < 20 ng/mL; >7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir p 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model. Results: TMPRSS2-ERG fusion by aCGH was identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis. Conclusions: In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.

Original languageEnglish (US)
Pages (from-to)5202-5209
Number of pages8
JournalClinical Cancer Research
Volume19
Issue number18
DOIs
StatePublished - Sep 15 2013
Externally publishedYes

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Image-Guided Radiotherapy
Prostatic Neoplasms
Radiotherapy
Comparative Genomic Hybridization
DNA Repair
Multivariate Analysis
Biopsy
Neoplasm Grading
Gene Fusion
DNA
Proportional Hazards Models
DNA Damage
Biomarkers
Recurrence

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy : Implications for fusion status anddsb repair. / Pra, Alan Dal; Lalonde, Emilie; Sykes, Jenna; Warde, Fiona; Ishkanian, Adrian; Meng, Alice; Maloff, Chad; Srigley, John; Joshua, Anthony M.; Petrovics, Gyorgy; Van Der Kwast, Theodorus; Evans, Andrew; Milosevic, Michael; Saad, Fred; Collins, Colin; Squire, Jeremy; Lam, Wan; Bismar, Tarek A.; Boutros, Paul C.; Bristow, Robert G.

In: Clinical Cancer Research, Vol. 19, No. 18, 15.09.2013, p. 5202-5209.

Research output: Contribution to journalArticle

Pra, AD, Lalonde, E, Sykes, J, Warde, F, Ishkanian, A, Meng, A, Maloff, C, Srigley, J, Joshua, AM, Petrovics, G, Van Der Kwast, T, Evans, A, Milosevic, M, Saad, F, Collins, C, Squire, J, Lam, W, Bismar, TA, Boutros, PC & Bristow, RG 2013, 'TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy: Implications for fusion status anddsb repair', Clinical Cancer Research, vol. 19, no. 18, pp. 5202-5209. https://doi.org/10.1158/1078-0432.CCR-13-1049
Pra, Alan Dal ; Lalonde, Emilie ; Sykes, Jenna ; Warde, Fiona ; Ishkanian, Adrian ; Meng, Alice ; Maloff, Chad ; Srigley, John ; Joshua, Anthony M. ; Petrovics, Gyorgy ; Van Der Kwast, Theodorus ; Evans, Andrew ; Milosevic, Michael ; Saad, Fred ; Collins, Colin ; Squire, Jeremy ; Lam, Wan ; Bismar, Tarek A. ; Boutros, Paul C. ; Bristow, Robert G. / TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy : Implications for fusion status anddsb repair. In: Clinical Cancer Research. 2013 ; Vol. 19, No. 18. pp. 5202-5209.
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abstract = "Background: Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50{\%} of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). Methods: Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) < 8, prostate-specific antigen (PSA) < 20 ng/mL; >7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir p 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model. Results: TMPRSS2-ERG fusion by aCGH was identified in 27 (21{\%}) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50{\%}) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis. Conclusions: In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.",
author = "Pra, {Alan Dal} and Emilie Lalonde and Jenna Sykes and Fiona Warde and Adrian Ishkanian and Alice Meng and Chad Maloff and John Srigley and Joshua, {Anthony M.} and Gyorgy Petrovics and {Van Der Kwast}, Theodorus and Andrew Evans and Michael Milosevic and Fred Saad and Colin Collins and Jeremy Squire and Wan Lam and Bismar, {Tarek A.} and Boutros, {Paul C.} and Bristow, {Robert G.}",
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TY - JOUR

T1 - TMPRSS2-ERG status is not prognostic following prostate cancer radiotherapy

T2 - Implications for fusion status anddsb repair

AU - Pra, Alan Dal

AU - Lalonde, Emilie

AU - Sykes, Jenna

AU - Warde, Fiona

AU - Ishkanian, Adrian

AU - Meng, Alice

AU - Maloff, Chad

AU - Srigley, John

AU - Joshua, Anthony M.

AU - Petrovics, Gyorgy

AU - Van Der Kwast, Theodorus

AU - Evans, Andrew

AU - Milosevic, Michael

AU - Saad, Fred

AU - Collins, Colin

AU - Squire, Jeremy

AU - Lam, Wan

AU - Bismar, Tarek A.

AU - Boutros, Paul C.

AU - Bristow, Robert G.

PY - 2013/9/15

Y1 - 2013/9/15

N2 - Background: Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). Methods: Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) < 8, prostate-specific antigen (PSA) < 20 ng/mL; >7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir p 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model. Results: TMPRSS2-ERG fusion by aCGH was identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis. Conclusions: In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.

AB - Background: Preclinical data suggest that TMPRSS2-ERG gene fusions, present in about 50% of prostate cancers, may be a surrogate for DNA repair status and therefore a biomarker for DNA-damaging agents. To test this hypothesis, we examined whether TMPRSS2-ERG status was associated with biochemical failure after clinical induction of DNA damage following image-guided radiotherapy (IGRT). Methods: Pretreatment biopsies from two cohorts of patients with intermediate-risk prostate cancer [T1/T2, Gleason score (GS) < 8, prostate-specific antigen (PSA) < 20 ng/mL; >7 years follow-up] were analyzed: (i) 126 patients [comparative genomic hybridization (CGH) cohort] with DNA samples assayed by array CGH (aCGH) for the TMPRSS2-ERG fusion; and (ii) 118 patients [immunohistochemical (IHC) cohort] whose biopsy samples were scored within a defined tissue microarray (TMA) immunostained for ERG overexpression (known surrogate for TMPRSS2-ERG fusion). Patients were treated with IGRT with a median dose of 76 Gy. The potential role of TMPRSS2-ERG status as a prognostic factor for biochemical relapse-free rate (bRFR; nadir p 2 ng/mL) was evaluated in the context of clinical prognostic factors in multivariate analyses using a Cox proportional hazards model. Results: TMPRSS2-ERG fusion by aCGH was identified in 27 (21%) of the cases in the CGH cohort, and ERG overexpression was found in 59 (50%) patients in the IHC cohort. In both cohorts, TMPRSS2-ERG status was not associated with bRFR on univariate or multivariate analysis. Conclusions: In two similarly treated IGRT cohorts, TMPRSS2-ERG status was not prognostic for bRFR, in disagreement with the hypothesis that these prostate cancers have DNA repair defects that render them clinically more radiosensitive. TMPRSS2-ERG is therefore unlikely to be a predictive factor for IGRT response.

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