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Human Molecular Genetics Advance Access published online on March 13, 2009
Human Molecular Genetics, doi:10.1093/hmg/ddp117
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© The Author 2009. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oxfordjournals.org

Identification of Interactive Networks of Gene Expression Associated with Osteosarcoma Oncogenesis by Integrated Molecular Profiling

Bekim Sadikovic1,#, Maisa Yoshimoto2,#, Susan Chilton-MacNeill1, Paul Thorner1, Jeremy A. Squire2,* and Maria Zielenska1

1 Department of Pediatric Laboratory Medicine, the Hospital for Sick Children, Toronto, Canada, M5G 1X8 2 Department of Pathology and Molecular Medicine, Richardson Labs, Queen's University, Kingston, Canada, K7L 3N6

* Corresponding Author: Jeremy A Squire, Ph.D. Department of Pathology and Molecular Medicine, Queens University, Kingston General Hospital, Richardson Laboratories, 88 Stuart Street, Queen's University, Kingston, Ontario, Canada, K7L 3N6. Tel: 613-533-2345, Fax: 613-533-6830 Email: squirej{at}queensu.ca

Received January 30, 2009; Revised February 19, 2009; Accepted March 9, 2009

Altered gene expression in tumours can be caused by copy number alterations to DNA or mutation affecting coding or regulatory regions of genes. However epigenetic events may also influence gene expression. Malignant cells can show major disruptions in DNA methylation profiles, which are manifested as aberrant hypermethylation or as hypomethylation of gene promoters, as well as global genomic hypomethylation. In this study we performed integrative whole-genome analysis of DNA copy number, promoter methylation and gene expression using 10 osteosarcomas. We identified significant changes including: hypomethylation, gain, and overexpression of histone cluster 2 genes at chromosome 1q21.1-q21.3; loss of chromosome 8p21.2-p21.3 and underexpression of DOCK5 and TNFRSF10A/D genes; and amplification-related overexpression of RUNX2 at chromosome 6p12.3-p21.1. Amplification and overexpression of RUNX2 could disrupt G2/M cell cycle checkpoints, and downstream osteosarcoma-specific changes such as failure of bone differentiation and genomic polyploidization. Failure of DOCK5-signaling, together with p53 and TNFRSF10A/D-related cell cycle and death pathways, may play a critical role in abrogating apoptosis. Our analyses show that the RUNX2 interactome may be constitutively activated in osteosarcoma, and that the downstream intracellular pathways are strongly associated with the regulation of osteoblast differentiation and control of cell cycle and apoptosis in osteosarcoma.

# equal contribution.


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