Riester Scott M, Torres-Mora Jorge, Dudakovic Amel, Camilleri Emily T, Wang Wei, Xu Fuhua, Thaler Roman R, Evans Jared M, Zwartbol René, Briaire-de Bruijn Inge H, Maran Avudaiappan, Folpe Andrew L, Inwards Carrie Y, Rose Peter S, Shives Thomas C, Yaszemski Michael J, Sim Franklin H, Deyle David R, Larson Annalise N, Galindo Mario A, Cleven Arjen G H, Oliveira Andre M, Cleton-Jansen Anne-Marie, Bovée Judith V M G, van Wijnen Andre J
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
J Orthop Res. 2017 May;35(5):1137-1146. doi: 10.1002/jor.23344. Epub 2016 Jun 28.
Osteoblastoma is a benign bone tumor that can often be difficult to distinguish from malignant osteosarcoma. Because misdiagnosis can result in unfavorable clinical outcomes, we have investigated microRNAs as potential diagnostic biomarkers for distinguishing between these two tumor types. Next generation RNA sequencing was used as an expression screen to evaluate >2,000 microRNAs present in tissue derived from rare formalin fixed paraffin embedded (FFPE) archival tumor specimens. MicroRNAs displaying the greatest ability to discriminate between these two tumors were validated on an independent tumor set, using qPCR assays. Initial screening by RNA-seq identified four microRNA biomarker candidates. Expression of three miRNAs (miR-451a, miR-144-3p, miR-486-5p) was higher in osteoblastoma, while the miR-210 was elevated in osteosarcoma. Validation of these microRNAs on an independent data set of 22 tumor specimens by qPCR revealed that miR-210 is the most discriminating marker. This microRNA displays low levels of expression across all of the osteoblastoma specimens and robust expression in the majority of the osteosarcoma specimens. Application of these biomarkers to a clinical test case showed that these microRNA biomarkers permit re-classification of a misdiagnosed FFPE tumor sample from osteoblastoma to osteosarcoma. Our findings establish that the hypoxia-related miR-210 is a discriminatory marker that distinguishes between osteoblastoma and osteosarcoma. This discovery provides a complementary molecular approach to support pathological classification of two diagnostically challenging musculoskeletal tumors. Because miR-210 is linked to the cellular hypoxia response, its detection may be linked to well-established pro-angiogenic and metastatic roles of hypoxia in osteosarcomas and other tumor cell types. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1137-1146, 2017.
骨母细胞瘤是一种良性骨肿瘤，常常难以与恶性骨肉瘤相区分。由于误诊会导致不良的临床结果，我们研究了微小RNA作为区分这两种肿瘤类型的潜在诊断生物标志物。下一代RNA测序用作表达筛选，以评估来自罕见的福尔马林固定石蜡包埋（FFPE）存档肿瘤标本的组织中存在的2000多种微小RNA。使用qPCR分析在独立的肿瘤组上验证了对这两种肿瘤具有最大区分能力的微小RNA。通过RNA-seq的初步筛选确定了四个微小RNA生物标志物候选物。三种miRNA（miR-451a、miR-144-3p、miR-486-5p）在骨母细胞瘤中的表达较高，而miR-210在骨肉瘤中升高。通过qPCR在22个肿瘤标本的独立数据集中对这些微小RNA进行验证，结果显示miR-210是最具区分性的标志物。这种微小RNA在所有骨母细胞瘤标本中表达水平较低，而在大多数骨肉瘤标本中表达强劲。将这些生物标志物应用于一个临床测试病例表明，这些微小RNA生物标志物能够将一个误诊的FFPE肿瘤样本从骨母细胞瘤重新分类为骨肉瘤。我们的研究结果表明，与缺氧相关的miR-210是区分骨母细胞瘤和骨肉瘤的鉴别标志物。这一发现提供了一种补充性分子方法，以支持对两种诊断具有挑战性的肌肉骨骼肿瘤进行病理分类。由于miR-210与细胞缺氧反应相关，其检测可能与缺氧在骨肉瘤和其他肿瘤细胞类型中已确立的促血管生成和转移作用有关。©2016骨科研究协会。由威利期刊公司出版。《矫形外科学研究杂志》35:1137 - 1146，2017年。
