An expression signature classifies chemotherapy-resistant pediatric osteosarcoma

Michelle B. Mintz, Rebecca Sowers, Kevin M. Brown, Sara C. Hilmer, Bethanne Mazza, Andrew G. Huvos, Paul A. Meyers, Bonnie LaFleur, Wendy S. McDonough, Michael M. Henry, Keri E. Ramsey, Cristina R. Antonescu, Wen Chen, John H. Healey, Aaron Daluski, Michael E. Berens, Tobey J. MacDonald, Richard Gorlick, Dietrich A. Stephan

Research output: Contribution to journalArticle

153 Citations (Scopus)

Abstract

Osteosarcoma is the most common malignant bone tumor in children. Osteosarcoma patients who respond poorly to chemotherapy are at a higher risk of relapse and adverse outcome. Therefore, it was the aim of this study to identify prognostic factors at the time of diagnosis to characterize the genes predictive of poor survival outcome and to identify potential novel therapeutic targets. Expression profiling of 30 osteosarcoma diagnostic biopsy samples, 15 with inferior necrosis following induction chemotherapy (Huvos I/II) and 15 with superior necrosis following induction chemotherapy (Huvos III/IV), was conducted using Affymetrix U95Av2 oligonucleotide microarrays. One hundred and four genes were found to be statistically significant and highly differentially expressed between Huvos I/II and III/IV patients. Statistically significant genes were validated on a small independent cohort comprised of osteosarcoma xenograft tumor samples. Markers of Huvos I/II response predominantly were gene products involved in extracellular matrix (ECM) microenvironment remodeling and osteoclast differentiation. A striking finding was the significant decrease in osteoprotegerin, an osteoclastogenesis inhibitory factor. Additional genes involved in osteoclastogenesis and bone resorption, which were statistically different, include annexin 2, SMAD, PLA2G2A, and TGFβ1. ECM remodeling genes include desmoplakin, SPARCL1, biglycan, and PECAM. Gene expression of select genes involved in tumor progression, ECM remodeling, and osteoclastogenesis were validated via quantitative reverse transcription-PCR in an independent cohort. We propose that osteosarcoma tumor-driven changes in the bone microenvironment contribute to the chemotherapy-resistant phenotype and offer testable hypotheses to potentially enhance therapeutic response.

Original languageEnglish (US)
Pages (from-to)1748-1754
Number of pages7
JournalCancer Research
Volume65
Issue number5
DOIs
StatePublished - Mar 1 2005

Fingerprint

Osteosarcoma
Pediatrics
Drug Therapy
Genes
Extracellular Matrix
Osteoprotegerin
Induction Chemotherapy
Osteogenesis
Necrosis
Desmoplakins
Biglycan
Annexins
Bone and Bones
Osteoclasts
Bone Resorption
Oligonucleotide Array Sequence Analysis
Heterografts
Reverse Transcription
Neoplasms
Phenotype

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Mintz, M. B., Sowers, R., Brown, K. M., Hilmer, S. C., Mazza, B., Huvos, A. G., ... Stephan, D. A. (2005). An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. Cancer Research, 65(5), 1748-1754. https://doi.org/10.1158/0008-5472.CAN-04-2463

An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. / Mintz, Michelle B.; Sowers, Rebecca; Brown, Kevin M.; Hilmer, Sara C.; Mazza, Bethanne; Huvos, Andrew G.; Meyers, Paul A.; LaFleur, Bonnie; McDonough, Wendy S.; Henry, Michael M.; Ramsey, Keri E.; Antonescu, Cristina R.; Chen, Wen; Healey, John H.; Daluski, Aaron; Berens, Michael E.; MacDonald, Tobey J.; Gorlick, Richard; Stephan, Dietrich A.

In: Cancer Research, Vol. 65, No. 5, 01.03.2005, p. 1748-1754.

Research output: Contribution to journalArticle

Mintz, MB, Sowers, R, Brown, KM, Hilmer, SC, Mazza, B, Huvos, AG, Meyers, PA, LaFleur, B, McDonough, WS, Henry, MM, Ramsey, KE, Antonescu, CR, Chen, W, Healey, JH, Daluski, A, Berens, ME, MacDonald, TJ, Gorlick, R & Stephan, DA 2005, 'An expression signature classifies chemotherapy-resistant pediatric osteosarcoma', Cancer Research, vol. 65, no. 5, pp. 1748-1754. https://doi.org/10.1158/0008-5472.CAN-04-2463
Mintz MB, Sowers R, Brown KM, Hilmer SC, Mazza B, Huvos AG et al. An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. Cancer Research. 2005 Mar 1;65(5):1748-1754. https://doi.org/10.1158/0008-5472.CAN-04-2463
Mintz, Michelle B. ; Sowers, Rebecca ; Brown, Kevin M. ; Hilmer, Sara C. ; Mazza, Bethanne ; Huvos, Andrew G. ; Meyers, Paul A. ; LaFleur, Bonnie ; McDonough, Wendy S. ; Henry, Michael M. ; Ramsey, Keri E. ; Antonescu, Cristina R. ; Chen, Wen ; Healey, John H. ; Daluski, Aaron ; Berens, Michael E. ; MacDonald, Tobey J. ; Gorlick, Richard ; Stephan, Dietrich A. / An expression signature classifies chemotherapy-resistant pediatric osteosarcoma. In: Cancer Research. 2005 ; Vol. 65, No. 5. pp. 1748-1754.
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AU - Antonescu, Cristina R.

AU - Chen, Wen

AU - Healey, John H.

AU - Daluski, Aaron

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