Genomic profiling of sporadic multiple meningiomas

Abstract

Background: Multiple meningiomas (MMs) rarely occur sporadically. It is unclear whether each individual tumor in a single patient behaves similarly. Moreover, the molecular mechanisms underlying the formation of sporadic MMs and clonal formation etiology of these tumors are poorly understood.

Methods: Patients with spatially separated MMs without prior radiation exposure or a family history who underwent surgical resection of at least two meningiomas were included. Unbiased, comprehensive next generation sequencing was performed, and relevant clinical data was analyzed.

Results: Fifteen meningiomas and one dural specimen from six patients were included. The majority of tumors (12/15) were WHO Grade I; one patient had bilateral MMs, one of which was Grade II, while the other was Grade I. We found 11/15 of our cohort specimens were of NF2-loss subtype. Meningiomas from 5/6 patients had a monoclonal origin, with the tumor from the remaining patient showing evidence for independent clonal formation. We identified a novel case of non-NF2 mutant MM with monoclonal etiology. MMs due to a monoclonal origin did not always display a homogenous genomic profile, but rather exhibited heterogeneity due to branching evolution.

Conclusions: Both NF2-loss and non-NF2 driven MMs can form due to monoclonal expansion and those tumors can acquire inter-tumoral heterogeneity through branched evolution. Grade I and II meningiomas can occur in the same patient. Thus, the molecular make-up and clinical behavior of one tumor in MMs, cannot reliably lend insight into that of the others and suggests the clinical management strategy for MMs should be tailored individually.

Keywords: Clonal formation; Genomics; Sporadic multiple meningiomas.

Fig. 1

Schematic summary of the study cohort. First top two panels represent the fraction of private and shared somatic alterations among the lesions of the same patient, CNVs and SNV/INDELs, respectively. Third panel annotation belongs to genomic subgroup with the clonal formation pattern concluded with the study, i.e. MC: Monoclonal formation, IND: Independent formation. Lower group panels summarize the clinical, histological and genomic attributes, such as age, sex, grade, histology, Ki-67 classification and location. SB: Skull Base, NSB: Non-Skull Base, AF: Anterior Fossa, MF: Middle Fossa, M: Midline, NM: Non-Midline, ANT: Anterior, POST: Posterior

Fig. 2

Representation of case S1. a MRI of 5 lesions, b hematoxylin and eosin (H&E) stain (magnification: 200×) for all 5 lesions, S1-T3: meningioma with psammomatous calcifications. c Phylogeny inferred from the somatic CNV, SNV/INDEL data of the lesions displaying monoclonal formation and branched evolution

Fig. 3

Representation of case S2. a MRI of the frontal (S2-T2) and the occipital lesion(S2-T1), b hematoxylin and eosin (H&E) stain (magnification: 200×) for both Grade II lesions, S2-T1: with chordoid features marked with black arrows. c Phylogeny inferred from the somatic CNV, SNV/INDEL of the 2 lesions

Fig. 4

Representation of case S5. a MRI of 2 lesions, b hematoxylin and eosin (H&E) stain (magnification: 200×) for both lesions, S5-T1: secretory meningioma with periodic acid Schiff positive pseudopsammoma bodies, black arrows. c Phylogeny inferred from the somatic CNV, SNV/INDEL of the 2 lesions