Genomic and epigenomic re-categorization of congenital glioblastoma and desmoplastic infantile ganglioglioma

The recently updated World Health Organization classification of Central Nervous System (CNS) tumors, 5 th edition, (CNS5) reclassifies pediatric tumors according to their distinct molecular drivers, recognizing a new entity - infant-type hemispheric glioma (IHG). Defined by its unique epigenetic signature, and/or genomic fusions in ALK, ROS1, NTRK or MET gene, IHG subsumes many cases previously classified as congenital glioblastoma (cGBM). Histologic features of IHG are still poorly defined with known overlap with a clinic-radiologically similar entity- desmoplastic infantile ganglioglioma / astrocytoma (DIG). We revisited our cohort of cGBMs and DIGs, now reclassifying them according to CNS5 and compared the clinical, radiologic and histologic features between the two. 3/6 cases of cGBM that underwent targeted NGS fusion mutation panel were positive for ALK fusions (involving MAP4, MZT2Bex2 and EML4 genes as fusion partners), and 1/6 showed GOPC:ROS1 fusion. Interestingly, GOPC:ROS1 fusion was also shared by 1/5 cases of histologically defined DIG. DNA methylation profiling using the Heidelberg classifier (v12.3) recategorized 2/5 DIG cases as IHG (including the case with ROS1 alteration). In conclusion, histology alone is insufficient to distinguish IHG from DIG, necessitating epigenomic and genomic testing for diagnosis of early-life gliomas.