Clinical Implications of the Genomic Profiling of Sporadic Multiple Meningiomas

Introduction: Multiple meningiomas (MMs) are typically observed in patients with a known familial predisposition due to a germline mutation and rarely occur sporadically. While MMs have been reported to be associated with more aggressive clinical behavior, it is unclear whether each individual tumor in a single patient behave similarly. Moreover, the molecular mechanisms underlying the formation of sporadic MMs are not understood and it is currently unknown if these tumors have a monoclonal origin or form independently. Thus, we sought to better understand the genomics of MMs to lend insight into their clinical management.

Methods: Patients with meningiomas that are spatially separated without an anatomical bridge (metachronous) without prior radiation exposure or a family history who underwent surgical resection of at least two meningiomas were included. All tumors underwent unbiased, comprehensive next generation sequencing. Relevant clinical data was retrieved and analyzed.

Results: Fifteen meningiomas and one dural specimen from six patients were included. The majority of tumors (12/15) were WHO Grade I; one of which was found to have an elevated proliferative index. Interestingly, one patient had bilateral sphenoid wing meningiomas, one of which was Grade II, while the other was Grade I. Only one patient had tumors localized to the same hemisphere. No tumors recurred during the median follow-up of 11.17 months. We found 73% of our cohort of MM specimens to have an underlying somatic NF2 mutation. Meningiomas from five out of six patients had a monoclonal origin, whereas the tumor from the remaining patient showed evidence for independent clonal formation. In one case in which dura from the uninvolved region in between MMs was available, we did not observe any meningioma driver somatic mutations. We, for the first time, identified a case of non-NF2 mutant multiple meningiomas with a monoclonal etiology. Meningiomas due to a monoclonal origin did not always display a homogenous genomic profile, but rather exhibited heterogeneity due to branching evolution, where some lesions acquired molecular alterations associated with more aggressive behavior.

Conclusion: Our findings reveal that sporadic MMs in the same patient can be heterogeneous in terms of both their histologic and genomic profiles. More specifically, both NF2 and non-NF2 driven MMs can form due to monoclonal expansion and those tumors can acquire intertumoral heterogeneity through branched evolution. Grade I and II meningiomas can occur in the same patient. Thus, the molecular make-up and potential clinical behavior of one tumor, in a patient with MMs, cannot reliably lend insight into that of the others. Therefore, the clinical management strategy for MMs should be tailored to each individual tumor based on its own presentation and natural history with recommendation for detailed genomic profiling of all tumors when surgery is performed.

Publication History

Article published online:
15 February 2022