PTHP-08. Integrated analysis of dysembryoplastic neuroepithelial tumors highlighting discrepancies between histopathological diagnosis and genome-wide DNA methylation profiling

BACKGROUND Dysembryoplastic neuroepithelial tumor (DNT) is a rare glioneuronal tumor that typically arises in childhood and is strongly associated with drug-resistant epilepsy. Diagnosis is often challenging due to histological heterogeneity. Therefore, DNT may be an ideal candidate for genome-wide DNA methylation profiling. However, integrated analyses combining histopathology and genome-wide DNA methylation profiling remain limited. METHODS We retrospectively analyzed the clinical data, histopathological diagnoses, and molecular findings of patients diagnosed with DNT or low-grade glioneuronal tumors mimicking DNT at the Japan Children’s Cancer Group Central Diagnosis between February 2016 and March 2025. RESULTS Twenty-three patients (12 males and 11 females) were included. The median age at the diagnosis was 11 years (range, 3 to 24 years). The majority were located in the temporal lobes (n=12) and other cortical regions (n=10), but a case was located in the third ventricle. Seizure onset was noted in 15 cases. FGFR1 tyrosine kinase domain internal tandem duplication was identified in 10 cases, and FGFR1 K656E mutation in 5 cases. Genome-wide DNA methylation profiling was available in 16 cases. According to the DKFZ classifier, 14 cases were classified as DNT, one as Pilocytic astrocytoma (PA), hemispheric, and one as Glioneuronal tumour, subtype A (novel). A case of PA, hemispheric was histopathologically diagnosed as DNT complex form and showed focal areas with PA morphology. Interestingly, a case of Glioneuronal tumour, subtype A (novel) showed atypical clinical features such as non-seizure onset and location in the third ventricle. It showed recurrence 5 years after an initial surgery with histopathological changes, including loss of specific glioneuronal elements and growth of multinucleated cells. CONCLUSIONS Discrepancy between histopathological diagnosis and DNA methylation classification may result from varied cellular composition. In addition, atypical DNA methylation classification may be associated with clinical signatures, requiring integrated analyses in larger cohorts.