RUNX1 and REXO2 are associated with the heterogeneity and prognosis of IDH wild type lower grade glioma

Haiwei Wang,Ji Zhang,Xinrui Wang,Liangpu Xu,Hua Cao

doi:10.1038/s41598-021-91382-1

Abstract

Based on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. However, the further classification of IDH wild type LGG was unclear. Here, IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster2 had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. Differentially expressed genes in sub-cluster1 were positively correlated with RUNX1 transcription factor. Moreover, IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster1 and associated with the worse prognosis of IDH wild type LGG. RUNX1 and REXO2 were associated with the higher immune infiltrations. Furthermore, RUNX1 and REXO2 were correlated with the worse prognosis of LGG or glioma. IDH wild type LGG in sub-cluster2 was hyper-methylated. REXO2 hyper-methylation was associated with the favorable prognosis of LGG or glioma. At last, we showed that, age, tumor grade and REXO2 expression were independent prognostic factors in IDH wild type LGG.

Highlights

Based on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups
Based on the global transcriptional profiling, those IDH wild type LGG patients were divided into two subclusters using “negative matrix factorization (NMF)” package in R software. 59 patients were classified into sub-cluster[1] and 37 patients were classified into sub-cluster[2] (Fig. 1a)
We identified 1317 genes were associated with the immune alterations in Chinese Glioma Genome Atlas (CGGA) dataset (Fig. 3a). 387 genes were differentially expressed in IDH wild type LGG patients in with different immune infiltrations in The Cancer Genome Atlas (TCGA) and CGGA datasets (Fig. 3a)

Summary

Introduction

Based on isocitrate dehydrogenase (IDH) alterations, lower grade glioma (LGG) is divided into IDH mutant and wild type subgroups. IDH wild type LGG patients in The Cancer Genome Atlas and Chinese Glioma Genome Atlas were divided into two sub-clusters using non-negative matrix factorization. IDH wild type LGG patients in sub-cluster[2] had prolonged overall survival and low frequency of CDKN2A alterations and low immune infiltrations. IDH wild type LGG patients with higher stromal score or immune score were positively correlated with RUNX1 transcription factor. RUNX1 and its target gene REXO2 were up-regulated in sub-cluster[1] and associated with the worse prognosis of IDH wild type LGG. IDH wild type LGG patients with TERT promoter mutation, EGFR amplification or H3F3A mutation have ever worse clinical outcomes[22]. Using “ConsensusClusterPlus” classification, IDH wild type LGG is divided into two sub-types with distinct clinical outcomes and immune alterations[28].

Methods

Results

Conclusion