Characteristics And Clinical Correlation Of N6-methyladenosine (m6A) In Adult IDH-mutant Diffuse Astrocytoma

Objective:As an important epigenetic modification,N6-methyladenosine(m6A)RNA methylation plays a key role in the tumorigenicity and malignant progression of multiple tumors;however,the biology function of m6 A in gliomas has not yet been fully elucidated.This study focused on adult-type IDH-mutant diffuse astrocytoma(WHO grades 2-4)to explore the prognostic value and characterization of m6 A regulators in IDH-mutant adult diffuse astrocytoma;to clarify the immune relationship between m6 A and IDH-mutant astrocytoma tumor microenvironment(TME),with aim to guide clinical treatment and improve patients’ prognosis.Methods:Extracting the transcriptome,mutational data,copy number variation,and clinical comprehensive data of 246 patients with IDH-mutant astrocytoma from The Cancer Genome Atlas(TCGA)and the China Glioma Genome Atlas(CGGA)database,23m6A-related gene expression characteristics and relevant clinical prognoses were evaluated.Unsupervised clustering of 23 m6A-related gene expressions identified m6 A modification patterns in IDH-mutant diffuse astrocytoma(WHO grades 2-4).Then,differences between groups were analyzed to obtain m6A-related differentially expressed genes(DEGs),and consistent clustering analysis and grouping were performed.Different m6 A modification patterns were distinguished between groups by principal component analysis and prognostic m6A-related DEG screening was performed.The expression of prognostic-related DEGs was analyzed by PCA and the m6 A score was calculated using the scoring model.The m6 A score was used to analyze the prognosis and evaluate its relationship with tumor microenvironment(TME)cell infiltration and immune response in IDH-mutant diffuse astrocytoma.and clinical prognoses.Results:Three subgroups of m6 A modifications distinct from clinical features and biological pathways were identified in 510 IDH-mutant diffuse astrocytomas.and characterized the mutational signature of IDH-mutant diffuse astrocytoma;and constructed an m6 A scoring model to evaluate the m6 A modification pattern of IDH-mutant diffuse astrocytoma based on 946 m6 A prognosis-related differentially expressed genes(DEGs)..The low m6 A score group was associated with better prognosis and immune response,the m6 A score was positively correlated with tumor mutational burden,and high TMB and high m6A scores predicted worse prognosis.The m6A score was correlated with the WHO grade,and recurrence and secondary tumors had higher m6 A scores.The m6 A low score group was more sensitive to cisplatin,vinblastine,dasatinib,and etoposide chemotherapy;conversely,the patients in m6 A high score group may benefit from PDGFR inhibitor imatinib and EGFR inhibitor gefitinib targeted therapies.Conclusion:This study explored the m6 A modification patterns of WHO grade 2-4 IDH-mutant astrocytoma,analyzed the correlation between m6A-related features and TME infiltration features,and analyzed the complex features of IDH-mutant astrocytoma TME,which is helpful for exploring the mechanism of its microenvironment and tumor proliferation and progression.The use of m6 A score provided an effective method for the description and analysis of clinically relevant characteristics of IDH-mutant astrocytoma patients,which can help predict patients’ prognoses,select potentially sensitive drugs,and provide more options for IDH-mutant astrocytoma treatment.