title: Identification of FoxR2 as an oncogene in medulloblastoma.
abstract: 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 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 medulloblastoma of the SHH subtype. Tgif2 and Alx4, 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 Gli1 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, 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 medulloblastoma.
authors.affiliation: Authors' Affiliations: Division of Molecular and Developmental Biology, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan; Division of Genetics and Genomics, Institute of Molecular and Cell Biology, Agency for Science, Technology and Research, Singapore, Singapore; Experimental Cancer Genetics, Wellcome Trust Sanger Institute, Hinxton, Cambridge, United Kingdom; and Cancer Research Program, The Methodist Hospital Research Institute, Houston, Texas.
authors.forename: Hideto
authors.initials: H
authors.lastname: Koso
authors.forename: Asano
authors.initials: A
authors.lastname: Tsuhako
authors.forename: Eli
authors.initials: E
authors.lastname: Lyons
authors.forename: Jerrold M
authors.initials: JM
authors.lastname: Ward
authors.forename: Alistair G
authors.initials: AG
authors.lastname: Rust
authors.forename: David J
authors.initials: DJ
authors.lastname: Adams
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Jenkins
authors.forename: Neal G
authors.initials: NG
authors.lastname: Copeland
authors.forename: Sumiko
authors.initials: S
authors.lastname: Watanabe
mesh_terms: D000818:Animals; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051858:Forkhead Transcription Factors / Q000096:biosynthesis / Q000235:genetics*; D057809:HEK293 Cells; D006801:Humans; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D041681:NIH 3T3 Cells; D009857:Oncogenes; D015398:Signal Transduction; D014162:Transfection
chemical_list: C499816:FOXR2 protein, human; D051858:Forkhead Transcription Factors; C499817:Foxr2 protein, mouse