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Basic and Translational Investigations |
Departments of Neurological Surgery (J.G.H., I.S., M.Y., S.H., J.S., S.R.V., M.S.B., C.D.J.), Epidemiology and Biostatistics (R.-F.Y.), and Pathology (S.R.V.), University of California, San Francisco, San Francisco, CA; Life Sciences Division, Lawrence Berkeley National Laboratory, Berkeley, CA (A.R., N.J.W., H.S.F., J.W.G., P.T.S.); USA
Address correspondence to J. Graeme Hodgson, Dept. of Neurological Surgery, University of California, San Francisco, San Francisco, CA 94143-0808, USA (ghodgson{at}cc.ucsf.edu).
Development of model systems that recapitulate the molecular heterogeneity observed among glioblastoma multiforme (GBM) tumors will expedite the testing of targeted molecular therapeutic strategies for GBM treatment. In this study, we profiled DNA copy number and mRNA expression in 21 independent GBM tumor lines maintained as subcutaneous xenografts (GBMX), and compared GBMX molecular signatures to those observed in GBM clinical specimens derived from the Cancer Genome Atlas (TCGA). The predominant copy number signature in both tumor groups was defined by chromosome-7 gain/chromosome-10 loss, a poor-prognosis genetic signature. We also observed, at frequencies similar to that detected in TCGA GBM tumors, genomic amplification and overexpression of known GBM oncogenes, such as EGFR, MDM2, CDK6, and MYCN, and novel genes, including NUP107, SLC35E3, MMP1, MMP13, and DDX1. The transcriptional signature of GBMX tumors, which was stable over multiple subcutaneous passages, was defined by overexpression of genes involved in M phase, DNA replication, and chromosome organization (MRC) and was highly similar to the poor-prognosis mitosis and cell-cycle module (MCM) in GBM. Assessment of gene expression in TCGA-derived GBMs revealed overexpression of MRC cancer genes AURKB, BIRC5, CCNB1, CCNB2, CDC2, CDK2, and FOXM1, which form a transcriptional network important for G2/M progression and/or checkpoint activation. Our study supports propagation of GBM tumors as subcutaneous xenografts as a useful approach for sustaining key molecular characteristics of patient tumors, and highlights therapeutic opportunities conferred by this GBMX tumor panel for testing targeted therapeutic strategies for GBM treatment.
Key Words: comparative genomics • GBM • xenograft
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