Abstract
Glioma is a primary high malignant intracranial tumor with poorly understood molecular mechanisms. Previous studies found that both DNA methylation modification and gene alternative splicing (AS) play a key role in tumorigenesis of glioma, and there is an obvious regulatory relationship between them. However, to date, no comprehensive study has been performed to analyze the influence of DNA methylation level on gene AS in glioma on a genome-wide scale. Here, we performed this study by integrating DNA methylation, gene expression, AS, disease risk methylation at position, and clinical data from 537 low-grade glioma (LGG) and glioblastoma (GBM) individuals. We first conducted a differential analysis of AS events and DNA methylation positions between LGG and GBM subjects, respectively. Then, we evaluated the influence of differential methylation positions on differential AS events. Further, Fisher’s exact test was used to verify our findings and identify potential key genes in glioma. Finally, we performed a series of analyses to investigate influence of these genes on the clinical prognosis of glioma. In total, we identified 130 glioma-related genes whose AS significantly affected by DNA methylation level. Eleven of them play an important role in glioma prognosis. In short, these results will help to better understand the pathogenesis of glioma.
Highlights
Glioma is the most common and highly malignant primary intracranial tumor which is characterized by substantial heterogeneity and extremely poor prognosis in central nervous system (CNS) (Dong and Cui 2020; Pan et al, 2021)
The results showed that the cis me-sQTLs of almost all types of alternative splicing (AS) events are significantly enriched in glioma risk methylation position dataset, i.e., Alternate Acceptors (AA) (OR = 4.76, p = 1.18 × 10–36), Alternate Terminators (AT) (OR = 2.85, p = 9.63 × 10–66), Exon Skip (ES) (OR = 2.39, p = 6.26 × 10–112), Retained Intron (RI) (OR = 2.05, p = 2.85 × 10–30), Alternate Donors (AD) (OR = 2.55, p = 4.78 × 10–21), and Alternate Promoters (AP) (OR = 2.88, p = 8.69 × 10–191), and there are a total of 130 genes whose cis me-sQTLs are significantly enriched in glioma risk methylation position dataset (p < 0.05)
By comparing the proportions of cis me-sQTLs and non me-sQTLs in each disease risk methylation position dataset, we found that the cis me-sQTLs significantly enriched the risk methylation position dataset of 103 diseases, which are mainly composed of CNS disorders and malignant tumor diseases including glioma (odds ratio (OR) = 2.49, p = 0)
Summary
Glioma is the most common and highly malignant primary intracranial tumor which is characterized by substantial heterogeneity and extremely poor prognosis in central nervous system (CNS) (Dong and Cui 2020; Pan et al, 2021). The annual incidence of this disease worldwide is about 5 cases per 100,000 people (Hottinger et al, 2014), and shows a significant mortality and unclarified molecular mechanism of the occurrence and development (Hottinger et al, 2014; Dong and Cui 2020). The DNA methylation has been demonstrated to extensively participate in the epigenetic mechanisms of CNS (Hwang et al, 2017), and many methyltransferase and demethylase-related genes (e.g., MGMT, CD44, HYAL2, SPP1, MMP2) contribute to the pathogenesis of glioma A large amount of the evidence showed that DNA methylation is involved in the occurrence and development of glioma tumors (Etcheverry et al, 2010; Chen et al, 2020; Dong and Cui 2020). The promoter methylation of DNA repair enzymes (O6-methylguanine-DNA methyltransferase) has been identified as a significant prognostic factor for temozolomide resistance in GBM patients (Chen et al, 2020)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
