Hypoxia-related microRNA-210 is a diagnostic marker for discriminating osteoblastoma and osteosarcoma.
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.
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Scott M
SM
Riester
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Jorge
J
Torres-Mora
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Amel
A
Dudakovic
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Emily T
ET
Camilleri
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.|Department of Orthopedic Surgery, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, P.R. China.
Wei
W
Wang
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Fuhua
F
Xu
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Roman R
RR
Thaler
Department of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, Minnesota.
Jared M
JM
Evans
Department of Pathology, Leiden University Medical Center in Leiden, Netherlands.
René
R
Zwartbol
Department of Pathology, Leiden University Medical Center in Leiden, Netherlands.
Inge H
IH
Briaire-de Bruijn
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Avudaiappan
A
Maran
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Andrew L
AL
Folpe
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Carrie Y
CY
Inwards
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Peter S
PS
Rose
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Thomas C
TC
Shives
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Michael J
MJ
Yaszemski
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Franklin H
FH
Sim
Department of Medical Genetics, Mayo Clinic, Rochester, Minnesota.
David R
DR
Deyle
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Annalise N
AN
Larson
Program of Cellular and Molecular Biology, Institute of Biomedical Sciences (ICBM), Faculty of Medicine, University of Chile, Santiago, Chile.|Millennium Institute on Immunology and Immunotherapy, University of Chile, Santiago, Chile.
Mario A
MA
Galindo
Department of Pathology, Leiden University Medical Center in Leiden, Netherlands.
Arjen G H
AGH
Cleven
Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota.
Andre M
AM
Oliveira
Department of Pathology, Leiden University Medical Center in Leiden, Netherlands.
Anne-Marie
AM
Cleton-Jansen
Department of Pathology, Leiden University Medical Center in Leiden, Netherlands.
Judith V M G
JVMG
Bovée
Department of Orthopedic Surgery, Mayo Clinic, 200 First Street SW, Rochester, Minnesota, 55905.
Andre J
AJ
van Wijnen
D015415:Biomarkers / Q000032:analysis; D001859:Bone Neoplasms / Q000737:chemistry / Q000175:diagnosis*; D003937:Diagnosis, Differential; D006801:Humans; D035683:MicroRNAs / Q000032:analysis*; D018215:Osteoblastoma / Q000737:chemistry / Q000175:diagnosis*; D012516:Osteosarcoma / Q000737:chemistry / Q000175:diagnosis*; D016133:Polymerase Chain Reaction; D017423:Sequence Analysis, RNA
D015415:Biomarkers; C543800:MIRN210 microRNA, human; D035683:MicroRNAs
FFPE; biomarker; microRNA; osteoblastoma; osteosarcoma