Data from Identification of FoxR2 as an Oncogene in Medulloblastoma

Abstract

<div>Abstract<p>Medulloblastoma is the most common pediatric brain tumor, and in ∼25% of cases, it is driven by aberrant activation of the Sonic Hedgehog (SHH) pathway in granule neuron precursor (GNP) cells. In this study, we identified novel medulloblastoma driver genes through a transposon mutagenesis screen in the developing brain of wild-type and <i>Trp53</i> mutant mice. Twenty-six candidates were identified along with established driver genes such as <i>Gli1</i> and <i>Crebbp</i>. The transcription factor <i>FoxR2</i>, the most frequent gene identified in the screen, is overexpressed in a small subset of human medulloblastoma of the SHH subtype. <i>Tgif2</i> and <i>Alx4</i>, 2 new putative oncogenes identified in the screen, are strongly expressed in the SHH subtype of human medulloblastoma. Mutations in these two genes were mutually exclusive with mutations in <i>Gli1</i> and tended to cooccur, consistent with involvement in the SHH pathway. Notably, Foxr2, Tgif2, and Alx4 activated Gli-binding sites in cooperation with Gli1, strengthening evidence that they function in SHH signaling. In support of an oncogenic function, <i>Foxr2</i> overexpression transformed NIH3T3 cells and promoted proliferation of GNPs, the latter of which was also observed for <i>Tgif2</i> and <i>Alx4</i>. These findings offer forward genetic and functional evidence associating <i>Foxr2</i>, <i>Tgif2</i>, and <i>Alx4</i> with SHH subtype medulloblastoma. <i>Cancer Res; 74(8); 2351–61. ©2014 AACR</i>.</p></div>