PATH-96. De Novo Mismatch Repair Deficiency in High Grade Gliomas: A Single Institution, Retrospective Experience

Abstract BACKGROUND Mutations in mismatch repair (MMR) genes (MSH2, MSH6, MLH1, and PMS2) are associated with microsatellite instability and a hypermutator phenotype. Hereditary MMRD-related conditions, including Lynch syndrome predispose patients to gliomas. We describe the clinical and molecular features of high-grade gliomas with a de novo mutation in the MMR genes. METHODS From glioma patients diagnosed between 2015-2025 at OHSU, adults with MMR deficiency on initial diagnosis and no history suspicious for genetic syndromes were identified. RESULTS Five patients (3 male, 2 female) had at least one MMR gene mutation in tumor tissue upon next-generation sequencing at initial diagnosis, accompanied by protein loss by immunohistochemistry. Median age at diagnosis was 45 years (range 34-57). Four patients had glioblastoma, IDH-wildtype, CNS WHO Grade 4. One patient had diffuse high-grade astrocytoma, IDH-wildtype, CNS WHO Grade 3 co-occurring with a separate IDH-mutant higher-grade glioma. One was MGMT hypermethylated, four were unmethylated. NGS showed that two patients had MSH2 and MSH6 mutations, two had MSH6 mutation, and one had MLH1 mutation. Tumor Mutation Burden (TMB) averaged 33 mutations/Mb (range 21-42.6). Other mutations included TP53 (4/5), NF1 (3/5), SETD2 (3/5), ATRX (2/5), TERT promotor region (2/5), and PIK3R1 (2/5). Most common presenting symptoms were generalized tonic-clonic seizures (3/5) followed by sensory changes, headaches, nausea and vomiting. All patients underwent surgical resection and 4/5 additionally received chemoradiation and temozolomide therapy. One patient with GBM received pembrolizumab immunotherapy in addition to bevacizumab, and one is on treatment. Germline testing for 2/5 patients revealed Lynch syndrome. DISCUSSION De novo MMRD high-grade glioma is a rare entity, associated with high TMB. Early detection, close surveillance, and adjuvant immunotherapy improve overall survival. Screening with germline testing for hereditary MMRD-related conditions is recommended when MMR-deficient gliomas are encountered. Limitations include small sample size and use of retrospective data.