背景:尽管脑膜瘤是常见的颅内肿瘤,多发性脑膜瘤(MMs)在没有2型神经肺癌的患者中是罕见的。先前的研究表明,大多数零星的MMs起源于单克隆。目的:利用下一代测序(NGS)平台阐明来自同一患者的两个散发性脑膜瘤之间的克隆关系。方法:两个MM,位于正面和顶部的右侧,手术切除了一名52岁的男性。对肿瘤样本进行病理检查和全外显子组测序,其次是Sanger测序验证。结果:MM被诊断为分泌型和纤维型亚型,分别,在组织学(WHOI级)和肿瘤DNA上表现出独特的体细胞突变模式。具体来说,分泌型亚型携带更多的单核苷酸变异,而纤维型亚型具有更高的拷贝数变异。此外,这两种肿瘤在易感基因和已知的驱动突变中表现出不同的突变特征.例如,分泌型亚型在TRAF7和KLF4中存在错义突变,而纤维型亚型除了NF2和SMARCB1的拷贝数丢失外,还存在NF2基因的移码缺失,这些遗传事件已经与脑膜瘤的发生有关.显著突变的基因分析揭示了分泌亚型中LOC729159和纤维亚型中RPGRIP1L和DPP6的新突变。Sanger测序验证了TRAF7中的重要点突变(c.1678G>A,p.G560S),KLF4(c.1225A>C,p.K409Q)和CDH11(c.169T>G,p.W57G)。结论:我们的数据表明,该患者可能独立发展为两种脑膜瘤,NGS的分子分型是常规病理的宝贵补充。需要进一步的研究来确定这些新的遗传事件是致瘤性的还是单纯的乘客突变。以及它们的临床意义。
Background: Although meningiomas are common intracranial tumors, multiple meningiomas (MMs) are rare entities in patients without neurofibromatosis type 2. Previous studies suggest most sporadic MMs are of monoclone in origin. Objective: To elucidate the clonal relationship between two sporadic meningiomas from the same patient by using the next-generation sequencing (NGS) platform. Methods: Two MMs, located frontally and parietally on the right side, were surgically removed from a 52-year-old male. Pathological examinations and whole exome sequencing were performed on tumor samples, followed by Sanger sequencing validation. Results: MMs were diagnosed as secretory and fibrous subtypes, respectively, on histology (WHO grade I) and tumor DNA exhibited distinctive somatic mutation patterns. Specifically, the secretory subtype carried more single nucleotide variant while the fibrous subtype had much higher copy number variation. Besides, the two tumors demonstrated different mutation profiles in predisposing genes and known driver mutations. For example, the secretory subtype had missense mutations in TRAF7 and KLF4, while the fibrous subtype had frameshift deletion of NF2 gene in addition to copy number loss of NF2 and SMARCB1, genetic events that have already been associated with the development of meningiomas. Significantly mutated gene analysis revealed novel mutations of LOC729159 in the secretory subtype and RPGRIP1L and DPP6 in the fibrous subtype. Sanger sequencing validated important point mutations in TRAF7 (c.1678G>A, p.G560S), KLF4 (c.1225A>C, p.K409Q) and CDH11 (c.169T>G, p.W57G). Conclusion: Our data suggest the two meningiomas might develop independently in this patient and molecular subtyping by NGS is a valuable supplement to conventional pathology. Further study is needed to ascertain whether these novel genetic events are tumorigenic or simply passenger mutations, as well as their clinical implications.