A Sleeping Beauty Forward Genetic Screen Identifies Genes Promoting Osteosarcoma Development and Metastasis

A Sleeping Beauty (SB) transposon forward genetic screen was performed to identify the genes that promote osteosarcoma (OS) development and metastasis. Mutagenesis induced OS in wild type mice and accelerated it on a Trp53 deficient background. Analysis of tumors demonstrated that Trp53 deficiency is correlated with genomic instability, which was virtually absent in tumors induced by SB mutagenesis alone. Metastases developed in a subset of animals and in nearly all cases were clonal related to primary tumors. Over 200 candidate genes were identified, many of which are altered in human cancers including OS. Signaling pathways enriched for candidate genes were also identified and a subset of these pathways and genes were functionally validated and represent new targets for OS treatment. Bisulphite converted DNA from the 21 diagnosis osteosarcoma patients and 3 hOB cell line replicates were hybridised to the Illumina Infinium 450K Human Methylation Beadchip.