Xu Zhijie, Gujar Hemant, Fu Guanghou, Ahmadi Hamed, Bhanvadia Sumeet, Weisenberger Daniel J, Jin Baiye, Gill Parkash S, Gill Inderbir, Daneshmand Siamak, Siegmund Kimberly D, Liang Gangning
Department of Urology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China.
USC Institute of Urology and Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, CA, United States.
Front Oncol. 2021 Feb 15;11:614927. doi: 10.3389/fonc.2021.614927. eCollection 2021.
Muscle-invasive bladder cancer (MIBC) accounts for approximately 20% of all urothelial bladder carcinomas (UBC) at time of diagnosis, and up to 30% of patients with non-muscle invasive UBC will progress to MIBC over time. An increasing body of evidence has revealed a strong correlation between aberrant DNA methylation and tumorigenesis in MIBC.
Using The Cancer Genome Atlas (TCGA) molecular data for 413 patients, we described a DNA methylation-based signature as a prognostic factor for overall survival (OS) in MIBC patients. By using a least absolute shrinkage and selection operator (LASSO) model, differentially methylated regions were first identified using multiple criteria followed by survival and LASSO analyses to identify DNA methylation probes related to OS and build a classifier to stratify patients with MIBC. The prognostic value of the classifier, referred to as risk score (RS), was validated in a held-out testing set from the TCGA MIBC cohort. Finally, receiver operating characteristic (ROC) analysis was used to compare the prognostic accuracy of the models built with RS alone, RS plus clinicopathologic features, and clinicopathologic features alone. We found that our seven-probe classifier-based RS stratifies patients into high- and low-risk groups for overall survival (OS) in the testing set (n = 137) (AUC at 3 years, 0.65; AUC at 5 years, 0.65). In addition, RS significantly improved the prognostic model when it was combined with clinical information including age, smoking status, Tumor (T) stage, and Lymph node metastasis (N) stage.
The DNA methylation-based RS can be a useful tool to predict the accuracy of preoperative and/or post-cystectomy models of OS in MIBC patients.
肌肉浸润性膀胱癌（MIBC）在诊断时约占所有尿路上皮膀胱癌（UBC）的20%，随着时间的推移，高达30%的非肌肉浸润性UBC患者会进展为MIBC。越来越多的证据表明，MIBC中异常DNA甲基化与肿瘤发生之间存在密切关联。
利用413例患者的癌症基因组图谱（TCGA）分子数据，我们描述了一种基于DNA甲基化的特征作为MIBC患者总生存期（OS）的预后因素。通过使用最小绝对收缩和选择算子（LASSO）模型，首先根据多个标准识别差异甲基化区域，然后进行生存分析和LASSO分析，以识别与OS相关的DNA甲基化探针，并构建一个分类器来对MIBC患者进行分层。该分类器的预后价值，即风险评分（RS），在来自TCGA MIBC队列的一个保留测试集中得到验证。最后，使用受试者工作特征（ROC）分析来比较仅用RS构建的模型、RS加临床病理特征构建的模型以及仅用临床病理特征构建的模型的预后准确性。我们发现，基于七探针分类器的RS在测试集（n = 137）中将患者分为总生存期（OS）的高风险和低风险组（3年时AUC为0.65；5年时AUC为0.65）。此外，当RS与包括年龄、吸烟状态、肿瘤（T）分期和淋巴结转移（N）分期在内的临床信息相结合时，显著改善了预后模型。
基于DNA甲基化的RS可以作为预测MIBC患者术前和/或膀胱切除术后总生存期模型准确性的有用工具。
