OTX2 is critical for the maintenance and progression of classic medulloblastoma

• Published in: Cancer research (Chicago, Ill.) Ill.), 2009-12, Vol.70 (1), p.181-191
• Main Authors: Adamson, David C., Shi, Qun, Wortham, Matthew, Northcott, Paul A., Di, Chunhui, Duncan, Christopher G., Li, Jianjun, McLendon, Roger E., Bigner, Darell D., Taylor, Michael D., Yan, Hai
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-09-2331

OTX2 is a developmentally regulated transcription factor that plays important roles in early morphogenesis of the central nervous system. We previously identified OTX2 amplification and overexpression in medulloblastoma cell lines. However, the nature and frequency of OTX2 genetic alterations have not been determined in large sample sizes of primary tumors. To refine our understanding of genomic events affecting OTX2 , we analyzed genomic copy number and mRNA expression of OTX2 in a large cohort of primary medulloblastomas. We found that the most frequent focal copy number gain in these primary medulloblastomas (gained in 21% of the tumors, n=201) contained the single gene OTX2 , indicating that copy number gain of OTX2 is a driver event in this tumor. In this cohort of tumors, we found that the event was restricted to tumor subtypes that do not express a molecular signature of either Wnt or Shh pathway activation. FISH analysis revealed that OTX2 copy number gain is present in a subset of cells within medulloblastoma samples, suggesting that it is a late event contributing to tumor progression. Gain of OTX2 copy number is associated with the presence of anaplastic histological features and shorter survival in medulloblastoma patients. To verify a functional role of the observed genomic events, we demonstrate that ectopic OTX2 expression enhances proliferation and tumorigenicity of immortalized primary cells and that OTX2 knockdown in medulloblastoma xenografts prolongs survival of recipient animals. Finally, we demonstrate that OTX2 transcriptionally upregulates the medulloblastoma oncogene MYC as a potential mechanism whereby OTX2 promotes tumor progression.