9534 Background: Despite the increased survival rates of osteosarcoma patients attributed to adjuvant chemotherapy, at least one third of the patients still succumb to their disease. Furthermore, ultra-aggressive combination chemotherapy is associated with considerable acute and long term toxicity. This is of particular concern in patients who may be cured by a simpler and less toxic regimens or do not have micrometastatic disease. Hence, further improvements in the management of osteosarcoma seemingly depend on diagnostic and prognostic tools that may allow for a more risk adapted and individualized treatment. Methods: We have used GE Uniset Human 20K microarrays to obtain gene expression profiles from a panel of ten unique human osteosarcoma xenografts. For each of the three drugs doxorubicin, cisplatin or ifosfamide the xenografts were grouped according to their response to chemotherapy, resistant, weakly sensitive or sensitive. For each individual drug, a one-way ANOVA test with a Benjamini and Hochberg multiple test correction allowing a false discovery rate of 5% (doxorubicin, cisplatin) or 2% (ifosfamide) was used to identify genes with significantly differential expression. In addition a 2-fold cut off was applied to exclude smaller but yet significant differences. Results: For doxorubicin and cisplatin, respectively 59 and 120 genes met these criteria. The expression levels of 25 genes overlapped between these two groups. For ifosfamide, 148 genes were selected, for 5 of them the expression overlapped with cisplatin sensitivity related genes. In the lists, genes involved in mediating and regulating apoptosis were abundant, such as regulators of TGF signaling, ubiquitin mediated protein degradation and members of the immediate early response protein family. Several genes which products interact with components of the cytoskeleton were also identified. Conclusion: We have used a unique strategy to screen for potential chemosensitivity markers by utilizing xenografts as training sets. No significant financial relationships to disclose.
Gene expression profiles of human osteosarcoma cell sublines with different pulmonary metastatic potentials
