HGG-50. LOW GRADE GLIOMA CAUGHT IN TRANSFORMATION: UTILITY OF COMPREHENSIVE GENOMIC PROFILING IN PEDIATRIC LI FRAUMENI SYNDROME ASSOCIATED HIGH-GRADE GLIOMA

Abstract BACKGROUND Diffuse paediatric-type high-grade glioma (HGG), H3-wildtype (WT) and IDH-WT have been recognised as a distinct subgroup in the 5th edition of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) (2021). METHODS We describe two patients with LFS with conflict between histological and molecular findings. They underwent integrated multi-omics to guide personalised therapy. RESULTS The first patient is a 10-year-old female with a left thalamic diffuse astrocytoma, histologically at least CNS WHO grade 2, with H3K27M, BRAFV600E and IDH1R132H negativity by immunohistochemistry (IHC) and retained H3K27me3, prompting initial management as a low-grade glioma. ZERO2 multi-omics profiling demonstrated no DNA methylation match, (v11b4 and 12.5), but loss of TP53 function (heterozygous germline mutation with tumour whole copy chromosome 17 loss); single copy chromosome X loss with BCOR mutation, and NF1 and FGFR1 mutations. However, tumor aneuploidy, IDH-WT status, co-segregated NF1 alteration and LFS suggested malignant transformation, leading to HGG treatment. The second patient is a 6-year-old boy with LFS, detected on cascade testing, after his brother’s diagnosis of bithalamic diffuse paediatric-type HGG MYCN, following cancer surveillance through Surveillance Study in Multi-organ Cancer Prone Syndrome (SMOC-Junior). Baseline whole-body MRI identified an asymptomatic bithalamic glioma, histopathologically compatible with low-grade astrocytoma except for mosaic loss of H3K27me3. DNA methylation matched (0.99) to diffuse pediatric-type HGG MYCN-subtype, with multiple copy number aberrations, EGFR amplification/overexpression, NF1 mutations and TP53 loss of heterozygosity, without MYCN-alteration or increased expression. He received HGG-specific radiation therapy and is on an NF1-targeted maintenance therapy with trametinib, a MEK inhibitor. In both cases, molecular features suggested early transformation. CONCLUSIONS These patients highlight that integrated multi-omic diagnostic approaches can identify transformation in TP53-altered low grade gliomas and inform development of personalised management guidelines for patients and families with Li Fraumeni syndrome.