GENES, CHROMOSOMES & CANCER 51:696–706 (2012) Identification of Osteosarcoma Driver Genes by Integrative Analysis of Copy Number and Gene Expression Data

High-grade osteosarcoma is a tumor with a complex genomic profile, occurring primarily in adolescents with a second peak at middle age. The extensive genomic alterations obscure the identification of genes driving tumorigenesis during osteosar-coma development. To identify such driver genes, we integrated DNA copy number profiles (Affymetrix SNP 6.0) of 32 diag-nostic biopsies with 84 expression profiles (Illumina Human-6 v2.0) of high-grade osteosarcoma as compared with its putative progenitor cells, i.e., mesenchymal stem cells (n 12) or osteoblasts (n 3). In addition, we performed paired anal-yses between copy number and expression profiles of a subset of 29 patients for which both DNA and mRNA profiles were available. Integrative analyses were performed in Nexus Copy Number software and statistical language R. Paired analyses were performed on all probes detecting significantly differentially expressed genes in corresponding LIMMA analyses. For both nonpaired and paired analyses, copy number aberration frequency was set to>35%. Nonpaired and paired integrative analyses resulted in 45 and 101 genes, respectively, which were present in both analyses using different control sets. Paired analyses detected>90 % of all genes found with the corresponding nonpaired analyses. Remarkably, approximately twice as many genes as found in the corresponding nonpaired analyses were detected. Affected genes were intersected with differen