Abstract 4917: PRKCE and other genetic networks in osteosarcoma metastasis

Abstract Osteosarcoma (OS) is the most common malignant bone cancer with approximately 1, 000 new cases reported annually in North America. Unfortunately OS has a poor 5-year survival rate (∼60%), and this is attributable largely to its propensity towards pulmonary metastasis: roughly a fifth (20%) of newly diagnosed cases are accompanied by macroscopic pulmonary metastases, and it is estimated that four fifths (80%) of all cases have undetectable microscopic metastases at diagnosis. The aim of the present study was to identify and characterize genetic networks that contribute to the metastasis of OS. Gene-expression profiling was performed on a cohort of 63 primary OS tumor samples: 46 with undetectable metastasis at diagnosis (‘localized’), and 17 that had detectable pulmonary metastasis at time of diagnosis (‘metastatic’). The relative abundance of transcripts from approximately 9, 000 genes was measured. This information was overlain on the Pathway Commons human interactome, and two independent methods of supervised network analysis were performed. Those networks with significantly differential gene expression, or ‘activity’ (Chuang et al. Mol. Sys. Biol. 2007), and those networks with significantly differential internal gene correlation, or ‘organization’ (Taylor et al. Nature Biotech. 2009) were discovered. Networks were assigned to biological processes using Gene Ontology Slim Generic. Real-time PCR was performed in vitro and in vivo to corroborate and validate the initial findings. The supervised network analysis has elucidated the 43 most significantly differentially activated, and 11 most significantly differentially organized networks in metastatic OS. One candidate differentially activated network, comprising RASGRP3, PRKCE and GNB2, was selected for follow-up. In vitro analysis in a panel of paired OS cell lines has corroborated the findings of the profiling screen: RASGRP3 was found to be under-expressed in some highly metastatic sub-lines, and PRKCE was found to be over-expressed in some highly metastatic sub-lines. Independent validation of PRKCE expression in the original tumor cohort has confirmed the increased expression in metastatic samples. A less stringent inspection of the network results reveals global trends in network aberrations: differentially activated networks are commonly found in transport, translation and protein modification processes, while dis-organized networks are commonly found in metabolism, signaling, transcription and organization processes. The study here described has revealed significant network aberrations in metastatic OS primary tumours. Additionally, several high-confidence networks have been identified for detailed follow-up. Subsequent in vitro and in vivo expression analysis has confirmed that one network is differentially expressed in metastatic OS. Knockdown assays are ongoing to demonstrate the impact of this network on OS metastatic progression. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4917. doi:10.1158/1538-7445.AM2011-4917

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