Identification of microRNA signature in different pediatric brain tumors

Abstract Understanding pediatric brain tumor biology is essential to help on disease stratification, and to find novel markers for early diagnosis. MicroRNA (miRNA) expression has been linked to clinical outcomes and tumor biology. Here, we aimed to detect the expression of different miRNAs in different pediatric brain tumor subtypes to discover biomarkers for early detection and develop novel therapies. Expression of 82 miRNAs was detected in 120 pediatric brain tumors from fixed-formalin paraffin-embedded tissues, low-grade glioma, high-grade glioma, ependymoma, and medulloblastoma, using quantitative real-time PCR. Low-expression of miR-221, miR-9, and miR-181c/d and over-expression of miR-101, miR-222, miR-139, miR-1827, and miR-34c was found in medulloblastoma; low expression of miR-10a and over-expression of miR-10b and miR-29a in ependymoma; low expression of miR-26a and overexpression of miR-19a/b, miR-24, miR-27a, miR- 584, and miR-527 in low-grade glioma. Cox regression showed differential miRNA expression between responders and non-responders. The most specific were miR-10a and miR-29a low expression in LGG non-responders, miR-135a and miR-146b over-expression in ependymoma non-responders, and miR-135b overexpression in medulloblastoma non-responders. MicroRNAs are differentially expressed in subtypes of brain tumors suggesting that they may help diagnosis. A greater understanding of aberrant miRNA in pediatric brain tumors may support development of novel therapies.

摘要：深入理解儿童脑肿瘤的生物学特性，对于疾病分层以及发掘早期诊断的新型标志物至关重要。微小核糖核酸（MicroRNA, miRNA）的表达与临床结局及肿瘤生物学特性密切相关。本研究旨在检测不同儿童脑肿瘤亚型中各类miRNA的表达水平，以发掘早期诊断用生物标志物并开发新型治疗手段。本研究采用实时荧光定量聚合酶链反应（qPCR），对120例来源于福尔马林固定石蜡包埋组织的儿童脑肿瘤样本中的82种miRNA表达水平进行了检测，所涉肿瘤亚型包括低级别胶质瘤、高级别胶质瘤、室管膜瘤及髓母细胞瘤。研究发现，髓母细胞瘤中miR-221、miR-9及miR-181c/d呈低表达，而miR-101、miR-222、miR-139、miR-1827及miR-34c呈高表达；室管膜瘤中miR-10a呈低表达，miR-10b与miR-29a呈高表达；低级别胶质瘤中miR-26a呈低表达，miR-19a/b、miR-24、miR-27a、miR-584及miR-527呈高表达。Cox回归分析表明，治疗应答者与非应答者的miRNA表达存在显著差异。其中特异性最强的标志物为：低级别胶质瘤非应答者中miR-10a与miR-29a的低表达，室管膜瘤非应答者中miR-135a与miR-146b的高表达，以及髓母细胞瘤非应答者中miR-135b的高表达。miRNA在不同脑肿瘤亚型中存在差异表达，提示其可辅助肿瘤诊断。进一步阐明儿童脑肿瘤中异常表达的miRNA，可为新型治疗手段的开发提供理论支撑。