Comparative gene set enrichment analysis (GSEA) of the embryonic stem cell (ES) gene signatures in canine and human osteosarcoma

Abstract

Osteosarcoma (OSA) is one of the most common malignancies in humans (especially children) and dogs. Canine OSA is considered an ideal model of human OSA because OSA in both species shares comparable oncogenic properties—including histopathological features, tumor biology, therapeutic approaches, and molecular mechanisms. In this study, we sought to compare the expression profiles of embryonic stem cell (ES) gene signatures in canine and human OSA tissues and cell lines. The expression patterns of three major ES gene signatures (modules or gene sets)—namely Myc, Core, and PRC modules—were primarily analyzed through the gene set enrichment analysis method in three gene expression datasets. For verification of the primary results, an additional 13 ES gene sets which were categorized into four groups—namely NOS targets, ES expressed, Myc targets, and Polycomb targets—were evaluated in expression datasets. Additionally, the prognostic efficacy of the gene sets with a similar enrichment pattern in humans and dogs was evaluated using the Cox proportional hazard model. Our results revealed that there were similar ES module expression patterns in the human OSA tissue and cell line, where the MYC modules, Myc targets, ES exp1, and NOS target modules were upregulated and the Polycomb target modules were downregulated in both entities. The canine OSA cell line showed ES enrichment patterns more similar to the patterns in its human counterpart, where we were able to detect the upregulation of the MYC modules, Myc targets, ES exp1, and NOS target modules and the downregulation of the Polycomb targets, including H3K27 bound and PRC2 targets. However, the canine OSA tissues presented a similar enrichment pattern at a lower degree than the canine OSA cell line. Furthermore, survival analysis identified the NOS targets as a more robust prognostic gene signature that efficiently predicted survival time in the human and canine OSA samples.

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