Assessment of the Diagnostic Utility of Serum MicroRNA Classification in Patients With Diffuse Glioma
Assessment of the Diagnostic Utility of Serum MicroRNA Classification in Patients With Diffuse Glioma
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DOI：
10.1001/jamanetworkopen.2019.16953
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发表时间：
2019-12-01
影响因子：
13.8
通讯作者：
Ochiya, Takahiro
中科院分区：
文献类型：
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作者：
Ohno, Makoto;Matsuzaki, Juntaro;Ochiya, Takahiro
研究弥漫性胶质瘤的血液筛查方法是提高临床预后的必要手段。目的：利用血清microrna建立模型，区分弥漫性胶质瘤患者和非肿瘤对照个体（胶质瘤指数），并区分胶质母细胞瘤（GBM）、原发性中枢神经系统淋巴瘤（PCNSL）和转移性脑肿瘤（3-肿瘤指数）。设计、环境和参与者：这项回顾性病例对照诊断研究纳入了2008年8月1日至2016年5月1日期间诊断的157例弥漫性胶质瘤患者和109例非弥漫性胶质瘤的中枢神经系统（CNS）疾病患者，以及314名性别和年龄匹配的无癌症对照。弥漫性胶质瘤患者和对照组样本随机分为训练和验证组1，非弥漫性胶质瘤的中枢神经系统疾病患者样本分配为探索组。GBM、PCNSL和转移性脑肿瘤患者样本随机分为训练组和验证组2。数据分析时间为2018年4月1日至2019年3月31日。评估2565个microrna的表达，并通过计算受试者工作特征曲线下面积（AUC）、敏感性、特异性和准确性来评估诊断性能。结果共纳入580例患者，其中男性309例（53.3%），中位年龄57岁（范围10 ~ 87岁）。在训练集1中，将100例弥漫性胶质瘤患者（年龄中位数为56岁[范围14-87岁]；55例男性[55.0%]）与200例对照患者（年龄中位数为56岁[范围14-87岁]；105例男性[52.5%]）进行比较，并使用3种microrna （miR-4763-3p， mir - 15% -3p和miR-3679-5p）构建胶质瘤指数。在验证集1中，AUC为0.99 (95% CI, 0.99-1.00)；灵敏度为0.95 (95% CI, 0.89-1.00)；特异性为0.97 （95% CI, 0.93-1.00）。在探索组中，胶质瘤指数将42例PCNSL样本中的39例（92.9%）和28例转移性脑肿瘤样本中的25例（89.3%）分类为阳性，2例脊柱肿瘤中2例（100%）为阴性。在训练集2中，对68例GBM患者、34例PCNSL患者和23例转移性脑肿瘤患者进行比较，使用48个microrna构建3-Tumor Index。3-Tumor Index的准确率为0.80，在验证集2中，17例GBM中有16例（94.1%），5例转移性脑肿瘤中有4例（80.0%），8例PCNSL中有4例（50.0%）阳性。结论和相关性这项研究似乎已经确定了有希望的血清microRNA组合，用于检测弥漫性胶质瘤和评估脑肿瘤的组织学特征。
IMPORTANCE A blood-based screening tool for detecting diffuse glioma is necessary to improve clinical outcomes.OBJECTIVES To establish models using serum microRNAs to distinguish patients with diffuse glioma from control individuals without cancer (the Glioma Index) and to differentiate glioblastoma (GBM), primary central nervous system lymphoma (PCNSL), and metastatic brain tumors (the 3-Tumor Index).DESIGN, SETTING, AND PARTICIPANTS This retrospective, case-control diagnostic study included 157 patients with diffuse glioma and 109 patients with central nervous system (CNS) diseases other than diffuse glioma diagnosed from August 1, 2008, through May 1, 2016, and 314 sex- and age-matched controls without cancer. Samples of patients with diffuse glioma and controls were randomly divided into training and validation set 1, and those of patients with CNS diseases other than diffuse glioma were allocated to an exploratory set. Samples of patients with GBM, PCNSL, and metastatic brain tumors were randomly divided into training and validation set 2. Data were analyzed from April 1, 2018, to March 31, 2019.MAIN OUTCOMES AND MEASURES The expression of 2565 microRNAs was assessed, and the diagnostic performance was evaluated by calculating the area under the receiver operating characteristics curve (AUC), sensitivity, specificity, and accuracy.RESULTS A total of 580 patients were included in the analysis (309 [53.3%] male; median age, 57 years [range, 10-87 years]). In training set 1, 100 patients with diffuse glioma (median age, 56 years [range, 14-87 years]; 55 male [55.0%]) were compared with 200 control patients (median age, 56 years [range, 14-87 years]; 105 male [52.5%]), and the Glioma Index was constructed using 3 microRNAs (miR-4763-3p, miR-1915-3p, and miR-3679-5p). In validation set 1, the AUC was 0.99 (95% CI, 0.99-1.00); sensitivity, 0.95 (95% CI, 0.89-1.00); and specificity, 0.97 (95% CI, 0.93-1.00). The Glioma Index classified 39 of 42 PCNSL samples (92.9%) and 25 of 28 metastatic brain tumor samples (89.3%) as positive and 2 of 2 spinal tumors (100%) as negative in the exploratory set. In training set 2, 68 patients with GBM, 34 with PCNSL, and 23 with metastatic brain tumor were compared, and the 3-Tumor Index was constructed using 48 microRNAs. The 3-Tumor Index had an accuracy of 0.80, positively detecting 16 of 17 GBM samples (94.1%), 4 of 5 metastatic brain tumor samples (80.0%), and 4 of 8 PCNSL samples (50.0%) in validation set 2.CONCLUSIONS AND RELEVANCE This study appears to have identified promising serum microRNA combinations for detecting diffuse glioma and for assessing histologic features of brain tumors.