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

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.

[1]  Michael Fraser,et al.  Genomic, pathological, and clinical heterogeneity as drivers of personalized medicine in prostate cancer. , 2015, Urologic oncology.

[2]  G. Sauter,et al.  The prognostic impact of high Nijmegen breakage syndrome (NBS1) gene expression in ERG‐negative prostate cancers lacking PTEN deletion is driven by KPNA2 expression , 2014, International journal of cancer.

[3]  Jeffrey R. Whiteaker,et al.  Proteogenomic characterization of human colon and rectal cancer , 2014, Nature.

[4]  A. Berlin,et al.  An arranged marriage for precision medicine: hypoxia and genomic assays in localized prostate cancer radiotherapy. , 2014, The British journal of radiology.

[5]  A. Jemal,et al.  Cancer statistics, 2013 , 2013, CA: a cancer journal for clinicians.

[6]  Arndt Hartmann,et al.  Expression of TIP60 (tat‐interactive protein) and MRE11 (meiotic recombination 11 homolog) predict treatment‐specific outcome of localised invasive bladder cancer , 2012, BJU international.

[7]  A Jakubowska,et al.  An inherited NBN mutation is associated with poor prognosis prostate cancer , 2012, British Journal of Cancer.

[8]  Charles A Enke,et al.  Prostate cancer, Version 3.2012: featured updates to the NCCN guidelines. , 2012, Journal of the National Comprehensive Cancer Network : JNCCN.

[9]  T. H. van der Kwast,et al.  Copy number alterations of c‐MYC and PTEN are prognostic factors for relapse after prostate cancer radiotherapy , 2012, Cancer.

[10]  R. Medeiros,et al.  DNA repair system and prostate cancer progression: the role of NBS1 polymorphism (rs1805794). , 2012, DNA and cell biology.

[11]  Dorota H. Sendorek,et al.  Epigenetic markers of prostate cancer in plasma circulating DNA. , 2012, Human molecular genetics.

[12]  A. Evans,et al.  Pathological predictors for site of local recurrence after radiotherapy for prostate cancer. , 2012, International journal of radiation oncology, biology, physics.

[13]  T. H. van der Kwast,et al.  NKX3.1 Haploinsufficiency Is Prognostic for Prostate Cancer Relapse following Surgery or Image-Guided Radiotherapy , 2011, Clinical Cancer Research.

[14]  Alvaro A. Martinez,et al.  TMPRSS2/ERG fusion gene expression alters chemo‐ and radio‐responsiveness in cell culture models of androgen independent prostate cancer , 2011, The Prostate.

[15]  G. Kristiansen,et al.  KPNA2 Expression Is an Independent Adverse Predictor of Biochemical Recurrence after Radical Prostatectomy , 2011, Clinical Cancer Research.

[16]  S. Elledge,et al.  The DNA damage response: making it safe to play with knives. , 2010, Molecular cell.

[17]  Ananya Choudhury,et al.  MRE11 expression is predictive of cause-specific survival following radical radiotherapy for muscle-invasive bladder cancer. , 2010, Cancer research.

[18]  C. Sander,et al.  Integrative genomic profiling of human prostate cancer. , 2010, Cancer cell.

[19]  Martin J. Aryee,et al.  Androgen-induced TOP2B mediated double strand breaks and prostate cancer gene rearrangements , 2010, Nature Genetics.

[20]  T. H. van der Kwast,et al.  High‐resolution array CGH identifies novel regions of genomic alteration in intermediate‐risk prostate cancer , 2009, The Prostate.

[21]  M. Pencina,et al.  Evaluating the added predictive ability of a new marker: From area under the ROC curve to reclassification and beyond , 2008, Statistics in medicine.

[22]  T. Dörk,et al.  ATM missense variant P1054R predisposes to prostate cancer. , 2007, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[23]  Kevin P. Murphy,et al.  Integrating copy number polymorphisms into array CGH analysis using a robust HMM , 2006, ISMB.

[24]  Rabab Kreidieh Ward,et al.  BMC Bioinformatics Methodology article A stepwise framework for the normalization of array CGH data , 2005 .

[25]  R. Bristow,et al.  Optimal treatment of intermediate‐risk prostate carcinoma with radiotherapy , 2005, Cancer.

[26]  R. Bristow,et al.  Defective DNA Strand Break Repair after DNA Damage in Prostate Cancer Cells , 2004, Cancer Research.

[27]  A. Jakubowska,et al.  NBS1 Is a Prostate Cancer Susceptibility Gene , 2004, Cancer Research.

[28]  J. Dahm-Daphi,et al.  Radiosensitivity of human tumour cells is correlated with the induction but not with the repair of DNA double-strand breaks , 2003, British Journal of Cancer.

[29]  Rafael A Irizarry,et al.  Exploration, normalization, and summaries of high density oligonucleotide array probe level data. , 2003, Biostatistics.

[30]  Charles A Enke,et al.  Featured Updates to the NCCN Guidelines , 2013 .

[31]  M. Roizen,et al.  Hallmarks of Cancer: The Next Generation , 2012 .

[32]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.