FREQUENT H3F3A K27M MUTATIONS IN THALAMIC GLIOMAS FROM YOUNG ADULT PATIENTS

Abstract

BACKGROUND: Mutations in the H3F3A gene, which encodes histone H3.3, were recently reported in cases of pediatric glioblastoma. H3F3A K27M mutations occur in gliomas that arise at midline locations, including the pons, thalamus, and spine; moreover, this particular mutation is found mainly in tumors in children and adolescents. In this study, we aimed to determine the association between H3F3A mutations and adult thalamic glioma. METHODS: Genomic H3F3A was sequenced from 20 separate thalamic gliomas. Additionally, for 14 of the 20 gliomas, 639 genes—including cancer-related genes and chromatin-modifier genes—were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome. RESULTS: Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 years; range, 17–46), and seven were from patients more than 50 years of age. Among the 18 high-grade thalamic gliomas, the H3F3A K27M mutation was present in 10 (91%) of the 11 tumors from patients under 50 years of age, and was absent in all seven tumors from patients over 50 years of age. The H3F3A K27M mutation was not detected in two diffuse astrocytomas. By additional sequencing, recurrent mutations were identified in TP53, ATRX, NF1 and EGFR. In addition, a KDM6A mutation was found in one case of diffuse astrocytoma and a CREBBP mutation was identified in one case of glioblastoma with the H3F3A K27M mutation. Gliomas with H3F3A K27M from pediatric or young-adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas. The patients with high-grade thalamic gliomas harboring the H3F3A K27M mutation that occur frequently in young adults had a poor prognosis similar to those with wild-type H3F3A tumors that occur mainly in older adults. CONCLUSIONS: We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.