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Objective: To investigate the clinicopathological and molecular features of meningioma, and to analyze the characteristic molecular changes in high-grade meningioma (WHO grades 2-3). Methods: A total of 139 meningioma specimens from 134 patients treated at Xuanwu Hospital, Capital Medical University from 2015 to 2020 were collected, including 49, 62 and 28 samples of WHO grades 1, 2 and 3 meningiomas, respectively. Clinical data and pathological diagnoses were reviewed. Next-generation sequencing (NGS) was conducted to analyze the associations of molecular biomarkers with clinicopathological features and prognosis. Results: Among the 134 patients, 59 patients (44.0%) were male, and 75 (56.0%) were female, age 57 (49, 66) years old. The most common genetic alteration was NF2 mutation (43.2%, 60/139). In non-NF2 mutated meningiomas, the hotspot genes of detectable mutations were AKT1 (13.7%, 19/139), TRAF7 (9.4%, 13/139), KLF4 (5.7%, 8/139), SMO (5.7%, 8/139), and PIK3CA (1.4%, 2/139). Twelve of the 13 cases TRAF7 alterations co-occurred with other genetic changes. Some molecular alterations were associated with histological subtypes. For instance, NF2 mutations were most frequently detected in psammomatous meningiomas (2/2) and fibrous meningiomas (8/9), while all secretory meningiomas harbored KLF4 mutations (6/6). Some molecular alterations were associated with tumor grade and prognosis. JAK3 mutations (4.3%, 6/139), TERT promoter mutations (3.6%, 5/139), and homozygous deletion of CDKN2A/B (4.3%, 6/139) were exclusively found in high-grade meningiomas. TERT promoter mutations and CDKN2A/B homozygous deletion (versus normal) were both independently associated with poorer prognosis (P<0.001 for both). JAK3 mutation was also associated with shorter overall survivals (P=0.031). Conclusions: NF2 is the most frequently mutated gene in meningiomas. TERT promoter mutations and CDKN2A/B homozygous deletion occur exclusively in high-grade meningiomas, link to unfavorable prognosis, and can serve as independent diagnostic markers for WHO grade 3 meningioma. JAK3 mutation seems also to be associated with high-grade meningiomas and shorter survivals.