Identification of FoxR2 as an oncogene in medulloblastoma
Menée à l'aide de modèles murins, cette étude identifie une surexpression du gène FoxR2 dans un sous-type de médulloblastome caractérisé par l'activation de la signalisation Sonic Hedgehog
Medulloblastoma (MB) 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 cells (GNPs). In this study, we identified novel MB driver genes through a transposon mutagenesis screen in the developing brain of wild-type and Trp53 mutant mice. Twenty-six candidates were identified along with established driver genes such as Gli1 and Crebbp. The transcription factor FoxR2, the most frequent gene identified in the screen, is overexpressed in a small subset of human MB of the SHH subtype. Tgif2 and Alx4, two new putative oncogenes identified in the screen, are strongly expressed in the SHH subtype of human MB. Mutations in these two genes were mutually exclusive with mutations in Gli1 and tended to co-occur, consistent with involvement in the SHH pathway. Notably, Foxr2, Tgif2 and Alx4 activated Gli-binding sites in cooperation with Gli1, strengthening evidence they function in SHH signaling. In support of an oncogenic function, Foxr2 overexpression transformed NIH3T3 cells and promoted proliferation of GNPs, the latter of which was also observed for Tgif2 and Alx4. These findings offer forward genetic and functional evidence associating Foxr2, Tgif2 and Alx4 with SHH subtype MB.