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
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.
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.
Oncotarget. 2014 Nov 30;5(22):11081-90. doi: 10.18632/oncotarget.2404.
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.
尽管使用了临床预后因素（前列腺特异性抗原、T分期和 Gleason评分），20%-60%的局限性前列腺癌（PCa）仍在初次局部治疗中失败。在此，我们确定了DNA损伤反应（DDR）主要传感器的预后重要性：MRE11A、RAD50、NBN、ATM、ATR和PRKDC。我们研究了接受图像引导放疗（IGRT；n=139）与根治性前列腺切除术（RadP；n=154）治疗的局限性PCa中DDR基因的拷贝数改变。在这两个队列中，NBN增益是最常见的基因组改变（分别为14.4%和11%的病例），并且与总体肿瘤基因组不稳定性相关（p<0.0001）。NBN增益是IGRT后5年无生化复发率（bRFR）的唯一显著预测因子（46%对77%；p=0.00067）。多变量分析显示，在调整已知临床预后变量后，NBN增益仍然是bRFR的显著独立预测因子（HR=3.28，95%CI 1.56-6.89，Wald p值=0.0017）。在RadP队列中，没有DDR传感基因具有预后意义。体外研究将NBN基因过表达与PCa细胞的放射抗性相关联。总之，NBN增益预测IGRT患者bRFR降低，但在RadP患者中并非如此。如果得到独立验证，Nibrin增益可能是首个PCa预测生物标志物，以促进使用手术或放疗的精准医学方法进行局部治疗决策。
