Tumor mutational burden is associated with poor outcomes in diffuse glioma

Lihong Wang,Yuanyuan Xu,Yu Shi,Xia Zhang,Yuhuan Tan,Song Deng,Ying Luo,Jia Ge,Wenying Wang,Mei Liang,Tao Luo,Yaoyao Tan,Yang Lan

doi:10.1186/s12885-020-6658-1

Lihong Wang, Yuanyuan Xu + Show 11 more

Open Access

https://doi.org/10.1186/s12885-020-6658-1

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Journal: BMC Cancer	Publication Date: Mar 12, 2020
Citations: 47	License type: open-access

Affiliation: Army Medical University, Southwest Hospital

Abstract

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

Highlights

Tumor mutational burden (TMB) is a potential biomarker for immune checkpoint therapy and prognosis
The mutation frequencies of IDH1 were higher in lower-grade gliomas (LGGs) than in GBM, and the mutation rates of PTEN and EGFR were higher in GBM than in LGG
We confirmed this conclusion through the analysis of mutational frequencies in LGG and GBM (IDH1, 77% vs 7%; PTEN, 5% vs 29%; EGFR, 5% vs 17%; Supplementary Figs. 1 and 2)

Summary

Introduction

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. Glioma is the most common malignant primary brain tumor in adults. Transcriptomics and methylomics has revealed the potential value of diagnosis based on molecules [1,2,3]. Exome sequencing or targeted sequencing is used to measure TMB. It is reported that panel-based TMB is highly correlated with TMB calculated by exome sequencing [9, 11]; panel-based TMB is commonly used in cancer patients to predict survival after immunotherapy [5]

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Conclusion