PTHP-10. Unveiling Adult-Type Gliomas in Pediatric and AYA Patients: Insights from Methylation Profiling

High grade gliomas (HGGs) in pediatric and adolescent/young adult (AYA) patients are typically classified as pediatric type tumors. However, emerging evidence challenges this age-based dichotomy, with some tumors in younger individuals exhibiting molecular features of adult-type gliomas. On routine histopathology and immunohistochemistry, these tumors are often labeled as HGG, NOS due to ambiguous morphology and lack of defining markers. We performed genome wide DNA methylation profiling on a cohort of 60 paediatric and AYA HGG, NOS cases diagnosed over a three year period (2020-2023). Classification was conducted using the DKFZ methylation Classifier, and integrated with immunohistochemistry, FISH, targeted sequencing, and copy number analysis. Thirteen of the 60 tumors (21.7%) arising in patients aged 1.5 to 39 years were reclassified as adult type gliomas based on methylation profiling. Ten tumors matched the methylation classes “glioblastoma, IDH-wildtype, RTK 1/2,” and three aligned with the recently recognized entity “adult type diffuse high-grade glioma, IDH wildtype, Subtype B”. None of the tumors harbored IDH1/2 mutations or 1p/19q codeletion. The canonical molecular landscape comprised TERT promoter mutations and EGFR amplification, hallmark alterations of glioblastomas. Activating mutations in BRAF, FGFR1, or NF1 - defining features of the MAPK pathway altered subset were consistently observed in adult type diffuse high grade glioma, IDH-wildtype, subtype B. Five of these 13 reclassified cases occurred in children aged ≤18 years. This is the first Indian study to demonstrate that adult type molecular gliomas including IDH wildtype glioblastomas and MAPK pathway altered adult type diffuse high-grade glioma can arise in pediatric and AYA patients. These tumors are frequently under recognized using standard histopathological evaluation but can be accurately identified through DNA methylation profiling. We advocate routine screening for MAPK alterations in all pediatric and AYA HGG with ambiguous features. The presence of actionable mutations such as BRAF, FGFR1, and TERT promoter variants underscores the potential for precision therapies, reinforcing the value of integrated molecular diagnostics across age groups.