Introduction: Adamantinomatous craniopharyngiomas (aCP) are usually driven genetically by mutations of the beta-catenin pathway. However, this does not explain the marked heterogeneity of the clinical disease. Therefore, we performed the first RNA deep-sequencing of aCP, to elucidate pathways implicated in its heterogeneous behavior.
Methods: aCp from our institutional biobank were histologically confirmed by an attending neuropathologist. Total RNA was extracted from each specimen and treated via established protocols to generate libraries for RNA whole-transcriptome deep-sequencing and analysis with the Illumina HiSeq 2500 platform. We also performed a clinical review of all patients collecting numerous variables.
Results: Twelve aCp underwent RNA deep-sequencing to an average depth of 37 million reads, with 50-70% of reads assigned to the human genome. Analysis between non-recurrent tumors and those that went on to recur identified VEGF, ANGPTL4, SOX7, and other RNA transcripts to be differentially expressed. Also, USP6, MYH3, KRT16, and ANGPTL7 were differentially expressed between patients diagnosed before and after age 30. Hierarchical clustering for both comparisons using respective differentially expressed genes elicited excellent separation between groups.
Conclusions: Deep-sequencing of the aCP transcriptome reveals novel molecular insights. We have elucidated clusters of RNA transcripts up- and down-regulated in aCp that later go on to recur. These pathways may drive the clinical heterogeneity of aCp and eventually allow for recurrence risk-stratification based on primary tumor analysis. Furthermore, we have identified a set of signaling pathways that are differentially expressed in aCp based on its bi-modal age distribution. This supports a unique molecular pathogenesis between aCp patient age groups.
Patient Care: Understanding the molecular pathophysiology of this rare but devastating tumor will allow for the advancement of adjuvant and neo-adjuvant treatments to improve surgical outcomes.
Learning Objectives: By the conclusion of this session, participants should be able to: 1) Describe the importance of different RNA-based molecular pathways in craniopharyngioma, 2) Discuss, in small groups the differences between various craniopharyngioma at the RNA level, 3) Identify effective future treatment targets using molecular analysis of craniopharyngioma