Comprehensive molecular characterization of adult H3K27M mutated thalamic glioma long-term survivors

Abstract

Abstract H3K27-altered diffuse midline gliomas (H3-DMGs) represent aggressive tumors with fatal outcome and exceedingly rare cases have a long-term survival (LTS). We included 5 adult thalamic H3-DMG LTS and 13 short-term survivors (STS), and performed whole exome sequencing, RNA-seq and DNA methylation array. The median overall survival was 48.0 ± 12.1 months for LTS and 12.5 ± 5.9 months for STS. There was no significant difference in clinical characteristics and treatment received between LTS and STS. LTS exhibited more copy number gain and amplification (P = 0.007), and tumor microenvironment analysis revealed increased accumulation of M1 macrophage (P = 0.005) alongside a notable reduction in cancer-associated fibroblast in LTS (P = 0.037). The signatures of LTS and STS were signature 30 (similarity = 76.7%) and signature 6 (81.8%), respectively. Of note, LTS exhibited hypermethylated CpG island (P = 0.002). Additionally, we demonstrated that LTS and STS could be distinguished using differentially methylated probes. Collectively, the present study delineated unique molecular characteristics of LTS H3-DMG.

Keywords

• H3K27-altered diffuse midline glioma
• Long-term survivor
• Mutation analysis
• RNA sequencing
• DNA methylation array