Hypoxia-related microRNA-210 is a diagnostic marker for discriminating osteoblastoma and osteosarcoma

Scott M. Riester, Jorge Torres-Mora, Amel Dudakovic, Emily T. Camilleri, Wei Wang, Fuhua Xu, Roman R. Thaler, Jared M. Evans, René Zwartbol, Inge H. Briaire-de Bruijn, Avudaiappan Maran, Andrew L. Folpe, Carrie Y. Inwards, Peter S. Rose, Thomas C. Shives, Michael J Yaszemski, Franklin H. Sim, David R Deyle, Annalise N. Larson, Mario A. GalindoArjen G H Cleven, Andre M. Oliveira, Anne Marie Cleton-Jansen, Judith V M G Bovée, Andre J van Wijnen

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
JournalJournal of Orthopaedic Research
DOIs
StateAccepted/In press - 2016

Fingerprint

Osteoblastoma
Osteosarcoma
MicroRNAs
Neoplasms
Biomarkers
Diagnostic Errors
Paraffin
Formaldehyde
RNA Sequence Analysis
Cell Hypoxia
Hypoxia
RNA
Bone and Bones

Keywords

  • Biomarker
  • FFPE
  • MicroRNA
  • Osteoblastoma
  • Osteosarcoma

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine

Cite this

Riester, S. M., Torres-Mora, J., Dudakovic, A., Camilleri, E. T., Wang, W., Xu, F., ... van Wijnen, A. J. (Accepted/In press). Hypoxia-related microRNA-210 is a diagnostic marker for discriminating osteoblastoma and osteosarcoma. Journal of Orthopaedic Research. https://doi.org/10.1002/jor.23344

Hypoxia-related microRNA-210 is a diagnostic marker for discriminating osteoblastoma and osteosarcoma. / 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.

In: Journal of Orthopaedic Research, 2016.

Research output: Contribution to journalArticle

Riester, SM, Torres-Mora, J, Dudakovic, A, Camilleri, ET, Wang, W, Xu, F, Thaler, RR, Evans, JM, Zwartbol, R, Briaire-de Bruijn, IH, Maran, A, Folpe, AL, Inwards, CY, Rose, PS, Shives, TC, Yaszemski, MJ, Sim, FH, Deyle, DR, Larson, AN, Galindo, MA, Cleven, AGH, Oliveira, AM, Cleton-Jansen, AM, Bovée, JVMG & van Wijnen, AJ 2016, 'Hypoxia-related microRNA-210 is a diagnostic marker for discriminating osteoblastoma and osteosarcoma', Journal of Orthopaedic Research. https://doi.org/10.1002/jor.23344
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. / Hypoxia-related microRNA-210 is a diagnostic marker for discriminating osteoblastoma and osteosarcoma. In: Journal of Orthopaedic Research. 2016.
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AU - Riester, Scott M.

AU - Torres-Mora, Jorge

AU - Dudakovic, Amel

AU - Camilleri, Emily T.

AU - Wang, Wei

AU - Xu, Fuhua

AU - Thaler, Roman R.

AU - Evans, Jared M.

AU - Zwartbol, René

AU - Briaire-de Bruijn, Inge H.

AU - Maran, Avudaiappan

AU - Folpe, Andrew L.

AU - Inwards, Carrie Y.

AU - Rose, Peter S.

AU - Shives, Thomas C.

AU - Yaszemski, Michael J

AU - Sim, Franklin H.

AU - Deyle, David R

AU - Larson, Annalise N.

AU - Galindo, Mario A.

AU - Cleven, Arjen G H

AU - Oliveira, Andre M.

AU - Cleton-Jansen, Anne Marie

AU - Bovée, Judith V M G

AU - van Wijnen, Andre J

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N2 - 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.

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