Tumor mutational burden is associated with poor outcomes in diffuse glioma

Abstract

Background

Tumor mutational burden (TMB) is a potential biomarker for immune checkpoint therapy and prognosis. The impact of TMB on clinical outcomes and the correlation coefficient between exome sequencing and targeted sequencing in glioma have not yet been explored.

Methods

Somatic mutations in the coding regions of 897 primary gliomas and the clinical and RNA-seq data of 654 patients in The Cancer Genome Atlas (TCGA) database were analyzed as a training set, while another 286 patients in the Chinese Glioma Genome Atlas (CGGA) database were used for validation. Descriptive and correlational analyses were conducted with TMB. Enrichment map analysis and gene set enrichment analysis (GSEA) were also performed.

Results

TMB was higher for the group of mutant genes that are frequently mutated in glioblastomas (GBMs) and lower for the group of mutant genes that are frequently mutated in lower-grade gliomas (LGGs). Patients with a higher TMB exhibited shorter overall survival. TMB was associated with grade, age, subtype and mutations affecting genomic structure. Moreover, univariate and multivariate analyses showed that TMB was an independent prognostic factor for glioma. The signaling pathways of the cell cycle were enriched in the TMB ^High group. TMB was higher in the mismatch repair (MMR) gene mutant group than in the wild-type group, but the MMR pathway was enriched in the TMB ^High group of gliomas without mutations in classical MMR genes. The correlation between TMBs calculated through exome sequencing and targeted sequencing was moderate, and panel-based TMB was not correlated with prognosis.

Conclusions

TMB is associated with poor outcomes in diffuse glioma. The high proliferative activity in the TMB ^High group could account for the shorter survival of these patients. This association was not reflected by a pan-cancer targeted sequencing panel.