PATH-56. Clinical and molecular features of diffuse gliomas with histone H3 gene pathogenic variants: A multicenter retrospective cohort study from the Kansai Molecular Diagnosis Network for CNS Tumors (KANSAI Network)

Abstract Diffuse gliomas sometimes harbor pathogenic variants (PVs) in the histone H3 gene. Tumors with H3 K27 PVs are typically found in midline lesions, while those with H3 G34 PVs are located in the cerebral hemisphere, classifying them as diffuse midline gliomas (DMG) and diffuse hemispheric gliomas (DHG), respectively. However, tumors with H3 K27 PVs have also been reported, albeit infrequently, in the cerebral hemisphere and are referred to as diffuse non-midline gliomas (NDMG). The distinct characteristics of gliomas with H3 PVs have yet to be fully elucidated. In this study, we conducted a retrospective analysis of the clinical, radiological, and molecular characteristics, as well as treatment outcomes, of patients with diffuse gliomas harboring H3 PVs. We collected 4,128 samples, including various primary and recurrent gliomas, from the 72 hospitals participating in the Kansai Network and identified 118 cases of patients with histone H3 PVs. Within this dataset, 93 patients were diagnosed with diffuse midline glioma (DMG), 16 with diffuse non-midline glioma (NDMG), and nine with diffuse hemispheric glioma (DHG). The age range for DMG cases was 4 to 78 years, with median progression-free survival (PFS) and overall survival (OS) times of 9.9 and 16.6 months, respectively. Favorable prognosis for DMG was associated with female sex, preoperative Karnofsky performance status (KPS) ≥80, adjuvant radiation plus temozolomide, and radiation dose ≥50 Gy. Patients with NDMG were older than those with DHG (median age: 45 vs. 25 years), while the OS times for NDMG cases were comparable to those of DHG (median OS: 20.0 vs. 22.5 months). Additionally, NDMGs exhibited DNA methylation patterns similar to those observed in DMGs. This study provides insights into the clinical and molecular characteristics of patients with H3 PVs in real-world settings, contributing to a deeper understanding of the pathology of diffuse gliomas with H3 PVs.