LGG-08. PROTEOGENOMICS REVEALS TWO DISTINCT BIOLOGICAL PILOCYTIC ASTROCYTOMA SUBGROUPS. (23rd April 2019)

• Record Type: Journal Article
• Authors: Picard, Daniel; Felsberg, Jörg; Langini, Maike; Pauck, David; Marquardt, Viktoria; Meyer, Frauke; Göbbles, Sarah; Stefanski, Anja; Stühler, Kai; Roque, Lucia; Borkhardt, Arndt; Reifenberger, Guido; Faria, Cláudia; Remke, Marc
• Is Part Of: Neuro-oncology. Volume 21(2019)Supplement 2
• Page Start: ii100
• Page End: ii100
• Publication Date: 2019-04-23
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noz036.151
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. Aberrant MAPK signaling, typically mediated by BRAF alterations, drives PA tumorigenesis. While five-year overall survival rates exceed 95%, tumor recurrence constitutes a major clinical challenge in incompletely resected tumors despite chemotherapeutic or radiation based therapeutic approaches. Therefore, we used proteogenomics to discern the biological heterogeneity of PA to improve classification of this tumor entity and identify novel therapeutic targets. Our proteogenomics approach integrates RNA sequencing, DNA methylation profiling and LC/MS-based proteomic profiling data from a cohort of 75 primary PA samples. Similarity Fusion Network (SNF) analysis was conducted to discern the biological heterogeneity of PA. Integrative genomics was used to identify aberrant pathway activation in these biological subgroups. Lastly, we utilized a drug screening pipeline to evaluate selective therapeutic activity of conventional anti-cancer and phase III/IV clinical trial drugs in PA culture models. Pilocytic astrocytomas segregate into two groups with distinct clinical and molecular features. Age is significantly associated with the SNF groups. BRAF fusions were predominantly observed in Group 1, while Group 2 PAs largely harbored other alterations leading to MAPK activation. Importantly, we could confirm these two distinct biological subgroups in two independent, non-overlapping cohorts. Pathway enrichment analyses reveal genesets involved in ion channel activity, neurotransmitter signaling and cellular respiration, whereas largely SYK-related immune response signatures are associated with Group 1. Confirming this analysis, the SYK inhibitor R788 was specifically active in Group 1 PAs, and less active in other brain tumor models (n=13).