HGG-56. EXTENSIVE MOLECULAR HETEROGENEITY WITHIN H3-/IDH-WILDTYPE PEDIATRIC GLIOBLASTOMA. (4th December 2020)

• Record Type: Journal Article
• Authors: Blattner-Johnson, Mirjam; Sahm, Felix; Sill, Martin; Sturm, Dominik; Kramm, Christof M; Pfister, Stefan M; Jones, David
• Is Part Of: Neuro-oncology. Volume 22(2020)Supplement 3
• Page Start: iii354
• Page End: iii354
• Publication Date: 2020-12-04
• Subjects: Brain Neoplasms -- Periodicals; Brain -- Tumors -- Periodicals; Brain -- Cancer -- Periodicals; Nervous system -- Cancer -- Periodicals; 616.99481
• DOI: 10.1093/neuonc/noaa222.335
• Languages: English
• ISSNs: 1522-8517

Abstract

Abstract: About half of all pediatric high-grade gliomas (HGG) harbor mutations in histone 3 or IDH genes. The remaining HGG are currently broadly classified as H3-/IDH-wild-type. Since the introduction of a uniform approach to DNA methylation-based classification of CNS tumors in 2018, DNA methylation data from over 45, 000 CNS tumor samples have been generated. From this large cohort, a number of smaller yet distinct subgroups start to emerge within H3-/IDH-wild-type HGG. Three such subgroups are enriched for focal gene amplifications and have been provisionally termed pedGBM_MYCN, pedGBM_RTK1 and pedGBM_RTK2. Since a significant subset of samples in each subgroup is lacking characteristic alterations, we further investigated the molecular and transcriptional composition of H3-/IDH-wild-type HGG. We evaluated DNA methylation and copy-number profiles in >1000 tumors classified as H3-/IDH-wild-type HGG. Tumors classified pedGBM_MYCN showed a focal MYCN amplification in 25%, with a similar fraction showing amplification of EGFR (8% of samples harbored both alterations) compared to 4% and 4% in pedGBM_RTK1 and 14% and 22% in pedGBM_RTK2. Deletion of CDKN2A/B was much more prevalent in the pedGBM_RTK2 subgroup (~50% compared to 27% in pedGBM_RTK1 and <10% in the pedGBM_MYCN group). We defined a pedGBM_MYCN transcriptional signature, which will be helpful in identifying subgroup-defining mechanisms and alterations. Initial results suggest an involvement of the sonic hedgehog pathway and genes controlling stem-cell pluripotency. Patient-derived xenograft models and murine neural stem cells are now being used for functional characterization and pre-clinical testing of potential drug targets in these molecularly defined subgroups.