P10.15.B CANCER PREDISPOSITION SYNDROMES IN PEDIATRIC PATIENTS WITH HIGH-GRADE GLIOMAS

Abstract BACKGROUND The association between pediatric high-grade gliomas (HGG) and cancer predisposition syndromes (CPS) remains inadequately elucidated in the existing literature, while next-generation sequencing (NGS) is increasingly utilized for diagnostic support MATERIAL AND METHODS In this retrospective analysis, we evaluated a cohort of 95 consecutive pediatric patients (48 males and 47 females), with a median age at tumor diagnosis of 10.4 year, with HGG reclassified according to the latest 2021 WHO classification, diagnosed and treated at the Bambino Gesù Children’s Hospital between 2011 and 2023. All patients underwent genetic germline testing with NGS technology to detect the presence of germline variants predisposing to cancer and were included in this study. RESULTS The cohort included 23 patients (24.2%) diagnosed with pHGG H3-IDH wild-type, 46 (48.4%) with diffuse midline glioma (DMG), and 7 (7.4%) with IDH-mutant astrocytoma. Anaplastic pleomorphic xanthoastrocytoma and adult-type HGG were each identified in 4 patients (4.2%), while neuroepithelial tumor with PATZ1 fusion was found in 3 patients (3.2%). HGG H3 G34-mutant and infant-type hemispheric glioma were each diagnosed in 2 patients (2.1%). Additionally, 4 patients (4.2%) had other rare histologies. Oncological family history was positive in 43/95 (45.3%) patients. Our analysis identified 80 variants across the 95 patients, categorized as follows: 7 pathogenic (P) variants, 12 likely pathogenic (LP) variants and 61 variants of uncertain significance (VUS). Notably, 23.7% of the P/LP variants were found in genes associated with CPS. While the distribution of these variants did not show significant differences across tumor subtypes, the highest proportion of pathogenic variants was observed in DMG. In addition, functional studies led to the reclassification of one LZTR1 variant from VUS to P, highlighting the importance of functional analysis in better interpreting variants initially classified as uncertain. CONCLUSION Notably, our results revealed that 18.9% of patients had P/LP variants, a rate higher than the 10% incidence typically reported in the literature. The high rate of mutations in CPS associated genes described in our work, leads to consider performing NGS even in the absence of clinical or anamnestic criteria suggestive of it. Moreover, further research are needed to determine the role of variants of uncertain significance