Adult-onset giant cell glioblastoma with biallelic PMS2 inactivation in Lynch syndrome

Abstract

Mismatch repair (MMR)-deficient glioblastomas represent a rare molecular subset with important hereditary and therapeutic implications. We report a 58-year-old man with adult-onset giant cell glioblastoma showing isolated PMS2 loss, microsatellite instability-high status, ultra-high tumor mutational burden, and confirmed biallelic PMS2 inactivation from a likely pathogenic germline PMS2 splice-site variant and somatic PMS2 nonsense mutation, revealing previously unrecognized Lynch syndrome. DNA methylation profiling classified the tumor as a high-grade glioma with MMR deficiency, with a methylation match to diffuse high-grade glioma, IDH-wildtype, subtype E. Given O⁶-methylguanine-DNA methyltransferase (MGMT) promoter unmethylation and MMR deficiency, temozolomide was omitted, and the patient received adjuvant radiation therapy with concurrent and maintenance pembrolizumab. Surveillance MRI at 5 months after gross total resection showed no evidence of recurrence. This case highlights giant cell morphology and ultra-high tumor mutational burden as potential clues to underlying MMR deficiency and supports consideration of reflex MMR immunohistochemistry, germline evaluation, and immune checkpoint inhibition in selected dMMR/MSI-H glioblastomas.