circNTRK2 protects NTRK2 expression in the distinct biological pilocytic astrocytoma subgroup 2

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Pilocytic astrocytoma (PA), the most common pediatric brain tumor, is primarily driven by aberrant mitogen-activated protein kinase (MAPK) signaling, most often due to BRAF gene fusions or activating mutations. While the five-year overall survival rate exceeds 95%, recurrence or progression remains a significant clinical challenge in cases where complete surgical resection is not possible. To better understand the molecular landscape of PA, we conducted an integrative multi-omics analysis using similarity network fusion (SNF) on RNA transcriptomic and mass spectrometry-based proteomic profiles from 62 patient tumor samples (Picard et al., Acta Neuropathologica 2023). Additionally, we now complementarily analyzed the circRNAome by identifying overlapping circRNAs across three independent detection algorithms in a subgroup-specific pattern. Our analysis revealed two distinct molecular subgroups, validated across three non-overlapping cohorts. Patients with Group 1 tumors were significantly younger and exhibited worse progression-free survival compared to those in Group 2. Pathway analyses (IPA and GSEA) indicated that Group 1 tumors were enriched in immune response pathways, particularly interferon signaling, whereas Group 2 tumors showed enrichment in action potential and neurotransmitter signaling pathways. Gene signature analysis further suggested higher T-cell infiltration in Group 1 compared to Group 2. Importantly, our recent findings revealed that Group 2 tumors displayed upregulation of both circular (circNTRK2) and linear NTRK2, with bioinformatic predictions suggesting that circNTRK2 may act as a miRNA sponge, preventing miRNA-mediated degradation of linear NTRK2. Current work focusses on the in vitro validation of the bioinformatically predicted functional network. These findings provide new insights into the biological diversity of PA, revealing molecular subgroups with potential prognostic relevance. This classification could improve risk stratification in this MAPK-driven tumor type, and our circRNA analysis suggests a novel mechanism of NTRK2 dysregulation potentially leading to aberrant MAPK signaling independent of previously described genetic alteration. key note lecture Dr. Romain Sigaud, PhD Department of Pediatrics and Adolescent Medicine, University Hospital, Comprehensive Cancer Center Central Germany (CCCG), Jena, Germany "Decoding the interplay between MAPK pathway dysregulation, oncogene-induced senescence, and tumor microenvironment in pediatric low-grade glioma" Publication History Article published online: 01 December 2025 © 2025. Thieme. All rights reserved. Georg Thieme Verlag KG Oswald-Hesse-Straße 50, 70469 Stuttgart, Germany

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