Cai Zhao, Chen Huang, Bai Jingqiao, Zheng Yang, Ma Jianhui, Cai Xiongwei, Liu Yu, Zhang Kaitai, Shou Jianzhong, Gao Yanning
State Key Laboratory of Molecular Oncology, Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.
Department of Pathology, China-Japan Friendship Hospital, Beijing, China.
Front Oncol. 2021 May 10;11:674933. doi: 10.3389/fonc.2021.674933. eCollection 2021.
Finding effective prognostic signatures is of great urgency due to the high risk of recurrence and progression of bladder cancer (BC). Although a lot of genetic alterations are involved in the carcinogenesis, none of them were referred in the current risk group stratifications. In this study, we aimed to find significant copy number variations (CNVs) to predict prognosis for BC patients.
CNVs with high aberration frequencies in BC were explored by array-based comparative genomic hybridization in 65 tumor samples. Candidates were validated in independent groups of BC tumor samples (n=219) and urine samples (n=123). 3D digital PCR was applied for detecting accurate gene copy numbers in BC urine. In order to explore the prognostic value of candidate CNVs, all enrolled patients were followed up for the disease-free survival (DFS). Cox proportional hazards regression analysis was performed to find the independent prognostic factors for DFS.
CNVs of CEP63, FOSL2 and PAQR6 with high aberration frequencies (67.7%, 56.9% and 60.0%, respectively) were found in BC tumors. Copy numbers of CEP63, FOSL2 and PAQR6 were gained in 219 tumor samples. CNVs of CEP63 and FOSL2 were correlated with advanced tumor stage and high grade. Retrospective analysis (median follow-up time: 69 months) revealed that CNVs of CEP63 and FOSL2 were independent prognostic factors for DFS of non-muscle-invasive bladder cancer (NMIBC) patients, while CNVs of FOSL2 and PAQR6 were independent prognostic factors for DFS of muscle-invasive bladder cancer (MIBC) patients. Models for predicting DFS were constructed based on CNVs of three genes. Patients with high prognostic indexes tended to have poor DFS. Prognostic index can also help to identify those with worse outcomes among high risk NMIBC patients. Copy number gains of CEP63 and FOSL2 in urine were found to be significantly correlated with poor DFS of NMIBC patients.
CNVs of CEP63, FOSL2 and PAQR6 were capable of predicting DFS and may serve as promising signatures for prognosis of BC.
由于膀胱癌（BC）复发和进展的高风险，寻找有效的预后特征迫在眉睫。尽管许多基因改变参与了致癌过程，但目前的风险分组分层中均未提及。在本研究中，我们旨在寻找显著的拷贝数变异（CNV）以预测BC患者的预后。
通过基于芯片的比较基因组杂交技术在65个肿瘤样本中探索BC中具有高畸变频率的CNV。候选基因在独立的BC肿瘤样本组（n = 219）和尿液样本组（n = 123）中进行验证。应用3D数字PCR检测BC尿液中准确的基因拷贝数。为了探索候选CNV的预后价值，对所有纳入的患者进行无病生存期（DFS）随访。进行Cox比例风险回归分析以寻找DFS的独立预后因素。
在BC肿瘤中发现了畸变频率较高的CEP63、FOSL2和PAQR6的CNV（分别为67.7%、56.9%和60.0%）。在219个肿瘤样本中CEP63、FOSL2和PAQR6的拷贝数增加。CEP63和FOSL2的CNV与肿瘤晚期和高分级相关。回顾性分析（中位随访时间：69个月）显示，CEP63和FOSL2的CNV是非肌肉浸润性膀胱癌（NMIBC）患者DFS的独立预后因素，而FOSL2和PAQR6的CNV是肌肉浸润性膀胱癌（MIBC）患者DFS的独立预后因素。基于三个基因的CNV构建了预测DFS的模型。预后指数高的患者DFS往往较差。预后指数还可帮助识别高危NMIBC患者中预后较差的患者。发现尿液中CEP63和FOSL2的拷贝数增加与NMIBC患者较差的DFS显著相关。
CEP63、FOSL2和PAQR6的CNV能够预测DFS，可能是BC预后的有前景的特征。
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