LGG-10. PROTEOGENOMICS DISCRIMINATES PEDIATRIC AND ADULT PILOCYTIC ASTROCYTOMA AS DISTINCT BIOLOGICAL ENTITIES. (31st May 2017)

• Record Type: Journal Article
• Authors: Picard, Daniel; Felsberg, Jörg; Langini, Maike; Pauck, David; Marquardt, Viktoria; Meyer, Frauke; Stefanski, Anja; Stühler, Kai; Borkhardt, Arndt; Reifenberger, Guido; Faria, Cláudia; Remke, Marc
• Is Part Of: Neuro-oncology. Volume 19(2017)Supplement 4
• Page Start: iv35
• Page End: iv35
• Publication Date: 2017-05-31
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/nox083.143
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Pilocytic astrocytoma (PA) is a well-circumscribed, slow growing, low-grade brain tumor predominantly affecting children and considered a single-pathway disease with activation of MAPK signaling, typically driven by BRAF alterations. While five-year overall survival rates exceed 95%, incompletely resected tumors recur frequently despite radiation and/or chemotherapy. Less favorable responses to multimodal therapies are observed in adults compared to pediatric patients. Thus, we utilized a proteogenomics approach to discern the biological heterogeneity of PA across all age-groups to identify novel therapeutic targets. Our proteogenomic approach encompasses RNA sequencing (RNAseq) and LC/MS-based proteomic profiling in a cohort of pediatric (n=55) and adult cases (n=24). Unsupervised hierarchical clustering is used to determine the biological heterogeneity of the disease. Integrative genomics, combined with downstream pathway analysis, dissects aberrant pathway activation in biological subgroups. Lastly, we utilize a drug screening pipeline encompassing conventional chemotherapeutics and targeted therapeutics (n=211) currently evaluated in phase III and IV clinical trials to validate novel molecular targets in PA culture models (n=8). Pediatric and adult PA segregate into two subgroups identified by unsupervised hierarchical clustering using RNAseq and proteomic profiling (p=0.001). Adult tumors form a single entity, while we observed additional heterogeneity in pediatric tumors segregating into two subgroups (p=0.01). Initial analyses show that adult PA demonstrate an over-representation of genes involved in translation initiation and ciliogenesis according to GeneSet Enrichment Analysis, whereas pediatric PA show a significant enrichment of pathways involved in glycolysis, signal transmission and AKT signaling. In all, our proteogenomic approach reveals important biological heterogeneity in pediatric and adult PA. Ongoing drug profiling is used to determine therapeutics with preferential activity against pediatric and adult PA cultures compared to neural stem cells and astrocytes. These biological insights may improve biological classification and reveal novel therapeutic targets specifically useful for non-resectable tumors with high risk of progressive disease.