Genetic alterations that deregulate RB and PDGFRA signaling pathways drive tumor progression in IDH2-mutant astrocytoma

<jats:title>Abstract</jats:title><jats:p>In <jats:italic>IDH</jats:italic>-mutant astrocytoma, <jats:italic>IDH2</jats:italic> mutation is quite rare and biological mechanisms underlying tumor progression in <jats:italic>IDH2</jats:italic>-mutant astrocytoma remain elusive. Here, we report a unique case of <jats:italic>IDH2</jats:italic> mutant astrocytoma, CNS WHO grade 3 that developed tumor progression. We performed a comprehensive genomic and epigenomic analysis for primary and recurrent tumors and found that both tumors harbored recurrent <jats:italic>IDH2</jats:italic><jats:sup><jats:italic>R172K</jats:italic></jats:sup> and <jats:italic>TP53</jats:italic><jats:sup><jats:italic>R248W</jats:italic></jats:sup> mutation with <jats:italic>CDKN2A/B</jats:italic> hemizygous deletion. We also found amplifications of <jats:italic>CDK4</jats:italic> and <jats:italic>MDM2</jats:italic> with <jats:italic>PDGFRA</jats:italic> gain in the recurrent tumor and upregulated protein expressions of these genes. We further developed, for the first time, a xenograft mouse model of <jats:italic>IDH2</jats:italic><jats:sup><jats:italic>R172K</jats:italic></jats:sup> and <jats:italic>TP53</jats:italic><jats:sup><jats:italic>R248W</jats:italic></jats:sup> mutant astrocytoma from the recurrent tumor, but not from the primary tumor. Consistent with parent recurrent tumor cells, amplifications of <jats:italic>CDK4</jats:italic> and <jats:italic>MDM2</jats:italic> and <jats:italic>PDGFRA</jats:italic> gain were found, while <jats:italic>CDKN2A/B</jats:italic> was identified as homozygous deletion in the xenografts, qualifying for integrated diagnosis of astrocytoma, IDH2-mutant, CNS WHO grade 4. Cell viability assay found that CDK4/6 inhibitor and PDGFR inhibitor potently decreased cell viability in recurrent tumor cells, as compared to primary tumor cells. These findings suggest that gene alterations that activate retinoblastoma (RB) signaling pathways and PDGFR may drive tumor progression and xenograft formation in <jats:italic>IDH2-</jats:italic>mutant astrocytoma, which is equivalent to progressive <jats:italic>IDH1</jats:italic>-mutant astrocytoma. Also, our findings suggest that these genomic alterations may represent therapeutic targets in <jats:italic>IDH2</jats:italic>-mutant astrocytoma.</jats:p>