PATH-14. Germline TP53 Mutations in Adult Diffuse Gliomas with IDH1 R132C Mutation: Investigating the Association with Li-Fraumeni Syndrome

Abstract BACKGROUND In adult-type diffuse gliomas, assessment of IDH mutations is essential for diagnosis. Most IDH1-mutant gliomas harbor the R132H variant, while rare variants such as R132C are less common. The IDH1 R132C variant has been linked to Li-Fraumeni syndrome (LFS), a hereditary cancer predisposition syndrome caused by germline TP53 mutations. However, the clinical approach to germline testing in R132C cases remains unclear. METHODS We retrospectively analyzed 99 patients with IDH-mutant gliomas treated at our institution from April 2006 to February 2025. IDH mutations were assessed using IHC, Sanger sequencing, HRM, and MLPA. TP53 mutations were evaluated by IHC and Sanger sequencing, and germline analysis was conducted using peripheral blood DNA. RESULTS Among the 99 cases, 96 (97%) had IDH1 mutations, with 3 (3%) harboring the R132C variant. All three R132C cases (male in his 40s, male in his 30s, female in her 20s) were 1p/19q non-codeleted, showed ATRX loss and TP53 positivity, and were diagnosed as astrocytoma, IDH-mutant, CNS WHO grade 2. Two cases had pathogenic TP53 mutations (c.845G>C and c.799C>T); one of these was also detected in the germline, resulting in a diagnosis of LFS despite not meeting classical clinical criteria. CONCLUSION Our findings suggest that germline TP53 testing should be considered in glioma patients with the IDH1 R132C mutation, even in the absence of a typical LFS clinical history. Accumulating further cases will be important to determine the prevalence of LFS in this molecular subset and may lead to refinement of LFS diagnostic criteria.