Otx2 Copy Number Gain Is A Driver Event In Shh-Independent Medulloblastomas

Proceedings: AACR 101st Annual Meeting 2010‐‐ Apr 17‐21, 2010; Washington, DC Medulloblastoma is the most common malignant brain tumor in children. With the exception of the Sonic Hedgehog (Shh) and Wnt pathways, the molecular events contributing to medulloblastoma tumorigenesis are poorly understood. In this study, we performed DNA copy number analysis upon a large cohort (n=201) of primary medulloblastomas to identify recurrent copy number events of these tumors. The most commonly gained region of the medulloblastoma genome (gained in 21% of tumors) contains the single gene OTX2, which encodes a developmental transcription factor involved in regionalization of the neural tube and specification of various CNS lineages. We found that OTX2 is also commonly overexpressed (74%, n=103) in these tumors. Molecular classification of medulloblastomas identified four distinct subtypes based on gene expression signature. OTX2 overexpression and copy number gain was limited to tumors not exhibiting a signature of Shh pathway activation. We found that OTX2 is necessary for intracranial xenograft formation by medulloblastoma cells and that its expression promotes xenograft tumor formation by immortalized primary cells. Finally, we determined that OTX2 regulates the medulloblastoma oncogene MYC. As a transcription factor, targeting OTX2 function with small molecules presents a challenge. However, retinoids can reduce OTX2 expression and inhibit medulloblastoma growth in vitro, and we have demonstrated that OTX2 silencing is required for this effect. In sum, these studies identify OTX2 as a common but targetable oncogene in Shh-independent medulloblastomas. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 233.