An expression signature classifies chemotherapy-resistant pediatric osteosarcoma Journal Article


Authors: Mintz, M. B.; Sowers, R.; Brown, K. M.; Hilmer, S. C.; Mazza, B.; Huvos, A. G.; Meyers, P. A.; LaFleur, B.; McDonough, W. S.; Henry, M. M.; Ramsey, K. E.; Antonescu, C. R.; Chen, W.; Healey, J. H.; Daluski, A.; Berens, M. E.; MacDonald, T. J.; Gorlick, R.; Stephan, D. A.
Article Title: An expression signature classifies chemotherapy-resistant pediatric osteosarcoma
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. ©2005 American Association for Cancer Research.
Keywords: osteosarcoma; signal transduction; cancer survival; child; human tissue; treatment outcome; bone neoplasms; osteolysis; survival rate; cisplatin; doxorubicin; validation process; chemotherapy; methotrexate; cancer diagnosis; phenotype; animals; mice; reverse transcription polymerase chain reaction; gene expression; gene expression profiling; smad protein; antineoplastic combined chemotherapy protocols; tumor markers, biological; cohort analysis; gene product; tumor biopsy; cell differentiation; drug resistance, neoplasm; mice, scid; necrosis; tumor marker; prediction; biopsy; childhood cancer; extracellular matrix; gene expression regulation, neoplastic; statistical significance; xenograft; rna, messenger; oligonucleotide array sequence analysis; quantitative analysis; gene identification; nucleotide sequence; transplantation, heterologous; transforming growth factor beta1; outcomes research; dna microarray; microenvironment; osteoclast; tumor growth; lipocortin 2; oligonucleotide; phospholipase a2; rna, neoplasm; osteoprotegerin; cd31 antigen; osteonectin; biglycan; desmoplakin
Journal Title: Cancer Research
Volume: 65
Issue: 5
ISSN: 0008-5472
Publisher: American Association for Cancer Research  
Date Published: 2005-03-01
Start Page: 1748
End Page: 1754
Language: English
DOI: 10.1158/0008-5472.can-04-2463
PUBMED: 15753370
PROVIDER: scopus
DOI/URL:
Notes: --- - "Cited By (since 1996): 96" - "Export Date: 24 October 2012" - "CODEN: CNREA" - "Molecular Sequence Numbers: GENBANK: AB008822, AL031058, D00017, J04599, M22430, MI4083, X86693;" - "Source: Scopus"
Altmetric Score
MSK Authors
  1. Wen Chen
    7 Chen
  2. Cristina R Antonescu
    612 Antonescu
  3. Paul Meyers
    247 Meyers
  4. John H Healey
    381 Healey
  5. Andrew G Huvos
    209 Huvos
  6. Bethanne Dorothy Wenzel
    20 Wenzel