Molecular characterization and genomic divergence in sporadic multiple meningiomas
Insa Prilop (Dresden), Majd Alkhatib (Dresden), Sylvia Herold (Dresden), Matthias Meinhardt (Dresden), Gabriele Schackert (Dresden), Ilker Y. Eyüpoglu (Dresden), Tareq Juratli (Dresden; Boston, MA / US)
Multiple meningiomas are rare and pose distinct management challenges. While the mutational landscape of single meningiomas has been extensively explored, the molecular pathogenesis of sporadic multiple meningiomas is not fully understood. The objective of this study is to elucidate the genetic characteristics of sporadic multiple meningiomas.
In our retrospective cohort from 2002 onwards, we identified 24 patients who underwent surgery for at least two sporadic separated meningiomas, totaling 57 meningiomas. Neurofibromatosis type 2 was excluded in all cases. We examined the genetic alterations in these tumors using a next generation sequencing (NGS), targeting a comprehensive set of genes frequently mutated in meningiomas, including AKT1, ATRX, CDKN2A, KLF4, NF1, NF2, PIK3CA, PIK3R1, POLR2A, PTEN, SMARCB1, SMO, STAG2, SUFU, TP53, TRAF7, and the TERT promotor. A radiological evaluation of MRI scans took place, applying a software with an automatic algorithm for segmentation (Brainlab AG, Munich, Germany).
The average age at initial diagnosis was 57 years (ranging from 34 to 82 years). The majority of these multiple meningiomas (94.7%) were classified as WHO grade 1. Within individual patients, no shared driver mutations were observed between separate tumors. Nearly all cases exhibited distinct hot spot mutations in well-known meningioma-driver genes, including TRAF7 (n=14), NF2 (n=9), KLF4 (n=5), PIK3CA (n=4), AKT1 (n=4), NF1 (n=1), SMO (n=2), SMARCB1 (n=1), POLR2A (n=1), PTEN (n=2), and the TERT promoter (n=1). Furthermore, meningiomas from the same patient frequently presented as different histopathological subtypes. Consistent with previous studies, separate tumors from the same patient displayed different driver mutations, suggesting independent origins and distinct genomic drivers. The review of an average of 2.6 MRI scans conducted prior to surgery revealed a median preoperative tumor size of 12.14 cm³ (ranging from 0.33 to 122 cm³). The smallest meningioma were those, which harbored a TRAF7 mutation (range from 0.33 to 36 cm³, average volume 5.7 cm³), while the largest meningiomas exhibited a NF2 mutation (range from 0.72 to 122 cm³, average volume 59.6 cm³).
Overall, our molecular analysis supports the notion of genomic divergence and the presumed independent origin of sporadic multiple meningiomas. This condition seems to exhibit both inter- and intra-personal heterogeneity.