目的:枕骨大孔(FM)脑膜瘤构成了重大的手术挑战,并且具有很高的发病率和死亡率。本研究旨在调查FM脑膜瘤中临床可行突变的分布,并确定与特定突变谱相关的临床特征。
方法:作者对来自三个国际机构的62个FM脑膜瘤进行了靶向下一代测序,涵盖所有相关脑膜瘤基因(AKT1、KLF4、NF2、POLR2A、PIK3CA,SMO,TERT启动子,和TRAF7)。患有辐射诱导的脑膜瘤或2型神经纤维瘤病(NF2)的患者被排除在研究之外。此外,患者和肿瘤特征,包括年龄,性别,放射学特征,和肿瘤的位置,进行回顾性收集和评估。
结果:研究队列包括46名女性和16名男性患者。在58例患者(93.5%)中检测到有临床意义的驱动突变。最常见的改变是TRAF7突变(26,41.9%),其次是AKT1E17K突变(19,30.6%)。两种突变均与相对于脑干的前外侧肿瘤位置显着相关(p=0.0078)。11例(17.7%)存在NF2突变,与肿瘤后部位置相关。与TRAF7和AKT1E17K突变的肿瘤相反。FM脑膜瘤的其他常见突变包括POLR2A突变(8,12.9%;6POLR2AQ403K和2POLR2AH439_L440del),KLF4K409Q突变(7,11.3%),和PIK3CA突变(4,6.5%;2个PIK3CAH1047R和2个PIK3CAE545K)。POLR2A和KLF4突变仅发生在女性患者中,与特定肿瘤位置没有显着关联。所有携带AKT1E17K和POLR2A突变的肿瘤均显示脑膜上皮组织学。十个肿瘤显示肿瘤内钙化,与AKT1突变型FM脑膜瘤相比,NF2突变型的频率明显更高(p=0.047)。
结论:这些发现为FM脑膜瘤的分子遗传学和临床病理特征提供了重要的见解。与肿瘤位置相关的特定遗传改变的鉴定,volume,钙化,组织学,诊断时的性别可能会对未来的个性化治疗策略产生影响。
OBJECTIVE: Foramen magnum (FM) meningiomas pose significant surgical challenges and have high morbidity and mortality rates. This study aimed to investigate the distribution of clinically actionable mutations in FM meningiomas and identify clinical characteristics associated with specific mutational profiles.
METHODS: The authors conducted targeted next-generation sequencing of 62 FM meningiomas from three international institutions, covering all relevant meningioma genes (AKT1, KLF4, NF2, POLR2A, PIK3CA, SMO, TERT promoter, and TRAF7). Patients with a radiation-induced meningioma or neurofibromatosis type 2 (NF2) were excluded from the study. Additionally, patient and tumor characteristics, including age, sex, radiological features, and tumor location, were retrospectively collected and evaluated.
RESULTS: The study cohort consisted of 46 female and 16 male patients. Clinically significant driver mutations were detected in 58 patients (93.5%). The most commonly observed alteration was TRAF7 mutations (26, 41.9%), followed by AKT1E17K mutations (19, 30.6%). Both mutations were significantly associated with an anterolateral tumor location relative to the brainstem (p = 0.0078). NF2 mutations were present in 11 cases (17.7%) and were associated with posterior tumor location, in contrast to tumors with TRAF7 and AKT1E17K mutations. Other common mutations in FM meningiomas included POLR2A mutations (8, 12.9%; 6 POLR2AQ403K and 2 POLR2AH439_L440del), KLF4K409Q mutations (7, 11.3%), and PIK3CA mutations (4, 6.5%; 2 PIK3CAH1047R and 2 PIK3CAE545K). POLR2A and KLF4 mutations exclusively occurred in female patients and showed no significant association with specific tumor locations. All tumors harboring AKT1E17K and POLR2A mutations displayed meningothelial histology. Ten tumors exhibited intratumoral calcification, which was significantly more frequent in NF2-mutant compared with AKT1-mutant FM meningiomas (p = 0.047).
CONCLUSIONS: These findings provide important insights into the molecular genetics and clinicopathological characteristics of FM meningiomas. The identification of specific genetic alterations associated with tumor location, volume, calcification, histology, and sex at diagnosis may have implications for personalized treatment strategies in the future.