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Introduction: We and others recently discovered that the homeobox transcription factor, OTX2, is amplified and overexpressed in a significant proportion of medulloblastomas, one of the most common malignant pediatric brain tumors. This gene plays a critical role in early neurodevelopment, and is minimally expressed postnatally. Furthermore, we previously demonstrated genetic and pharmacologic inhibition of OTX2 resulted in reduced cell viability in vitro. Medulloblastoma histology subtypes do not uniformly correlate with prognosis or treatment response to highly toxic adjuvant therapies in this young patient population. Therefore, better prognostic markers are needed to predict survival and identify patients that need the most aggressive therapies. This study evaluated the role of OTX2 as a novel molecular prognostic marker. Methods: OTX2 expression was evaluated in medulloblastoma cell lines and primary tumors by immunoblot, immunohistochemistry, and florescent in situ hybridization (FISH) analyses. OTX2 immunohistochemistry and gene copy number in primary tumors were compared to clinical and histological variables using standard Kaplan Meier survival analysis techniques. Results: OTX2 expression was detected in 67% (8/12) of medulloblastoma cell lines and increased copy number by FISH was demonstrated on double minutes in three cell lines. OTX2 expression was detected in 45% (37/83) of primary tumor samples by immunohistochemistry. Increased OTX2 copy number by FISH was seen in anaplastic primary tumors from which OTX2+ cell lines were derived. OTX2 expression by immunohistochemistry and FISH analysis significantly correlated with shorter survival, anaplasia, and age < 3 years. Conclusions: OTX2, a new medulloblastoma oncogene, is an important molecular prognositc marker that correlates with anaplasia and patient survival. Additionally, this novel prognostic tumor marker may improve currently inadequate treatment stratification schemes.

[Proc Amer Assoc Cancer Res, Volume 47, 2006]