H3F3A K27M mutations in thalamic gliomas from young adult patients

Abstract

Introduction: Mutations in H3F3A, which encodes histone H3.3, commonly occur in pediatric glioblastoma. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. Here, we sought 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 y; range, 17-46), and 7 were from patients over 50 years of age. The H3F3A K27M mutation was present in 10 of the 11 (91%) younger patients and absent from all 7 older patients. Additionally, H3F3A K27M was not detected in the 2 diffuse astrocytomas. Further sequencing revealed recurrent mutations in TP53, ATRX, NF1, and EGFR. 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.

Conclusion: We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.

Keywords: H3F3A mutation.; thalamic glioma; young adult.

Fig. 1.

Nonsynonymous mutations identified via targeted sequencing. Each row represents a specific gene, and each column represents one sample. The shaded boxes represent identified nonsynonymous mutations.

Fig. 2.

Heatmap of methylation levels (β-value) in 150 high-grade gliomas, including 14 thalamic gliomas analyzed in this study. Supervised clustering was performed using 8000 selected Infinium probes. Each row represents a probe, each column represents one sample. For each sample, annotation of methylation cluster and H3F3A mutation status are indicated by colored boxes at the bottom of the map.

Fig. 3.

Kaplan–Meier estimates of overall survival in cases of high-grade thalamic gliomas. There was no statistical difference in overall survival between patients with H3F3A K27M-mutant tumors and those with wild-type H3F3A tumors.