Yin Ming, Grivas Petros, Emamekhoo Hamid, Mendiratta Prateek, Ali Siraj, Hsu JoAnn, Vasekar Monali, Drabick Joseph J, Pal Sumanta, Joshi Monika
Department of Medicine, Division of Hematology-Oncology, Penn State Cancer Institute, Hershey, PA, USA.
Department of Medicine, Division of Oncology, Ohio State University Comprehensive Cancer Center, Columbus, OH, USA.
Oncotarget. 2018 Mar 30;9(24):16891-16898. doi: 10.18632/oncotarget.24738.
Mutations of DNA repair genes, e.g. , are frequently found in urothelial cancer (UC) and have been associated with better response to cisplatin-based chemotherapy. Further external validation of the prognostic value of mutations in UC can inform clinical decision making and trial designs.
In the discovery dataset, mutations were present in 24% of patients and were associated with shorter OS (adjusted HR 2.67, 95% CI, 1.45-4.92, = 0.002). There was a higher mutation load in patients carrying mutations (median mutation load: 6.7 versus 5.5 per Mb, = 0.072). In the validation dataset, mutations were present in 22.2% of patients and were non-significantly associated with shorter OS (adjusted HR 1.87, 95% CI, 0.97-3.59, = 0.06) and higher mutation load (median mutation load: 8.1 versus 7.2 per Mb, = 0.126).
Exome sequencing data of 130 bladder UC patients from The Cancer Genome Atlas (TCGA) dataset were analyzed as a discovery cohort to determine the prognostic value of mutations. Results were validated in an independent cohort of 81 advanced UC patients. Cox proportional hazard regression analysis was performed to calculate the hazard ratio (HR) and 95% confidence interval (CI) to compare overall survival (OS).
mutations may be a biomarker of poor prognosis in unselected UC patients and may correlate with higher mutational load. Further studies are required to determine factors that can further stratify prognosis and evaluate predictive role of mutation status to immunotherapy and platinum-based chemotherapy.
DNA修复基因的突变，例如，在尿路上皮癌（UC）中经常被发现，并且与基于顺铂的化疗的更好反应相关。对UC中突变的预后价值进行进一步的外部验证可以为临床决策和试验设计提供信息。
在发现数据集中，24%的患者存在突变，并且与较短的总生存期相关（调整后的风险比2.67，95%置信区间，1.45 - 4.92，P = 0.002）。携带突变的患者有更高的突变负荷（中位突变负荷：每兆碱基6.7对5.5，P = 0.072）。在验证数据集中，22.2%的患者存在突变，并且与较短的总生存期（调整后的风险比1.87，95%置信区间，0.97 - 3.59，P = 0.06）和更高的突变负荷（中位突变负荷：每兆碱基8.1对7.2，P = 0.126）无显著关联。
对来自癌症基因组图谱（TCGA）数据集的130例膀胱UC患者的外显子测序数据进行分析作为发现队列，以确定突变的预后价值。结果在81例晚期UC患者的独立队列中得到验证。进行Cox比例风险回归分析以计算风险比（HR）和95%置信区间（CI）来比较总生存期（OS）。
突变可能是未选择的UC患者预后不良的生物标志物，并且可能与更高的突变负荷相关。需要进一步的研究来确定可以进一步分层预后的因素，并评估突变状态对免疫疗法和基于铂的化疗的预测作用。
