DNA methylation pattern of brain stem pilocytic astrocytomas in children

Abstract

10021 Background: Pilocytic astrocytoma (WHO grade I) comprises the most frequent brain tumor in childhood. We were recently able to identify BRAF as a centrally important oncogene in these tumors showing duplication or activation in a majority of cases. Although histologically indistinguishable, tumors with brain stem location have a particularly poor prognosis. It is not well established, whether this is due to their close proximity to pivotal anatomic sites or due to distinct biological characteristics. Methods: To identify novel genes involved in astrocytoma pathogenesis, we performed a genome-wide DNA methylation analysis of 78 pilocytic astrocytoma samples from different tumor locations (diencephalic, cerebral, cerebellar, brain stem). BeadChip methylation technology was used to identify genes showing differential promoter methylation among tumors. Two CpG sites were analyzed for each of a total of 14.000 promoters per sample. Clinical and molecular subgroups were compared using Significance Analysis of Microarrays (SAM). Results: In this genome-wide approach, we identified an 11-gene signature that was able to correctly separate all brain stem tumors (n = 8) from the majority of tumors from other locations (56/70). Moreover, from 14 tumors clustering together with the brain stem tumors, 5 patients experienced disease recurrence (38%) as opposed to 20% in the remaining group. Genes contained in the signature most interestingly included three homeobox family genes (HOXB1, HOXD3, and HOXD4), and NES, a tumor stem cell marker. Conclusions: These data suggest that brain stem pilocytic astrocytomas display biologic features different from most tumors of other locations and share a methylation signature with tumors prone to disease recurrence from other locations. We provide first evidence for a role of differentially methylated homeobox family genes in the pathogenesis of pilocytic astrocytoma. No significant financial relationships to disclose.