OTX2 is critical for the maintenance and progression of Shh-independent medulloblastomas.
OTX2 is a developmentally regulated transcription factor involved in early morphogenesis of the central nervous system. This gene is amplified and overexpressed in medulloblastoma cell lines, but the nature and extent of its genetic alterations in primary tumors have not been evaluated. Analysis of a large cohort of primary medulloblastomas revealed frequent focal copy number gain of a region minimally containing OTX2 as a single gene. OTX2 copy number gain was restricted to tumor subtypes that did not express a molecular signature of Wnt or Shh pathway activation. FISH analysis revealed copy number gain in a subset of cells within medulloblastoma samples, suggesting a late event in tumor progression. Gain of OTX2 copy number was associated with the presence of anaplastic histologic features and shorter survival in medulloblastoma patients. In support of a functional role, ectopic OTX2 expression enhanced proliferation and tumorigenicity of immortalized primary cells, whereas OTX2 knockdown in medulloblastoma cells prolonged the survival of animals bearing xenograft tumors. Mechanistic investigations revealed upregulation of MYC as a potential mechanism whereby OTX2 promotes tumor progression. Our findings define OTX2 as an important oncogenic driver in medulloblastoma.
Adamson
David C
DC
Department of Surgery, The Pediatric Brain Tumor Foundation Institute, and The Preston Robert Tisch Brain Tumor Center at Duke, Duke University Medical Center, Veterans Affairs Medical Center, Durham, North Carolina 27710, USA.
Shi
Qun
Q
Wortham
Matthew
M
Northcott
Paul A
PA
Di
Chunhui
C
Duncan
Christopher G
CG
Li
Jianjun
J
McLendon
Roger E
RE
Bigner
Darell D
DD
Taylor
Michael D
MD
Yan
Hai
H
D000818:Animals; D015153:Blotting, Western; D002528:Cerebellar Neoplasms / Q000235:genetics* / Q000378:metabolism; D018450:Disease Progression; D018628:Gene Dosage; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc / Q000235:genetics; D053823:Hedgehog Proteins / Q000235:genetics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008527:Medulloblastoma / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020411:Oligonucleotide Array Sequence Analysis; D051857:Otx Transcription Factors / Q000235:genetics*; D016133:Polymerase Chain Reaction; D020641:Polymorphism, Single Nucleotide
D053823:Hedgehog Proteins; C497659:OTX2 protein, human; D051857:Otx Transcription Factors; C509239:SHH protein, human