The multiomic landscape of meningiomas: a review and update

Abstract

Purpose Meningiomas are the most common primary brain tumor in adults. Traditionally they have been understudied compared to other central nervous system (CNS) tumors. However over the last decade, there has been renewed interest in uncovering the molecular topography of these tumors, with landmark studies identifying key driver alterations contributing to meningioma development and progression. Recent work from several independent research groups have integrated different genomic and epigenomic platforms to develop a molecular-based classification scheme for meningiomas that could supersede histopathological grading in terms of diagnostic accuracy, biological relevance, and outcome prediction, keeping pace with contemporary grading schemes for other CNS tumors including gliomas and medulloblastomas. Methods Here we summarize the studies that have uncovered key alterations in meningiomas which builds towards the discovery of consensus molecular groups in meningiomas by integrating these findings. These groups supersede WHO grade and other clinical factors in being able to accurately predict tumor biology and clinical outcomes following surgery. Results Despite differences in the nomenclature of recently uncovered molecular groups across different studies, the biological similarities between these groups enables us to likely reconciliate these groups into four consensus molecular groups: two benign groups largely dichotomized by NF2-status, and two clinically aggressive groups defined by their hypermetabolic transcriptome, and by their preponderance of proliferative, cell-cycling pathways respectively. Conclusion Future work, including by our group and others are underway to validate these molecular groups and harmonize the nomenclature for routine clinical use.

Independent prognostic impact of DNA methylation class and chromosome 1p loss in WHO grade 2 and 3 meningioma undergoing adjuvant high-dose radiotherapy: comprehensive molecular analysis of EORTC 22042–26042

“…Deletions of CDKN2A/B were detected three times (2 homozygous losses and 1 heterozygous loss), 1p loss 23 times (60.5%) and 22q losses 29 times (76.3%). The frequency of observed events was generally similar to larger meningioma cohorts [ 10 ]. Most cases were identified as intermediate meningioma MC (44.7%), followed by malignant (28.9%) and benign (26.3%) MC (molecular events per MC in Suppl.…”

“…Specifically, mutations in the promotor area of the telomerase reverse transcriptase ( TERT ) gene and/or homozygous loss of the CDKN2A/B locus automatically result in a grade 3 diagnosis [ 3 , 4 ]. Simultaneously meningioma with TRAF7 , AKT1 , KLF4 , and/or SMO mutations are, in general, associated with lower progression risk [ 1 , 10 ]. Alterations linked with increased risk include BAP1 mutations [ 9 ], copy-number variations of chromosomal arms such as 1p, 6q, 10q and 14q [ 6 ], genome-wide epigenetic profiles also referred to as DNA methylation classes (MC) [ 8 ], or the combination of molecular alterations included in an integrated risk score, grade or classification [ 2 , 5 , 7 ].…”

Grading meningioma resections: the Simpson classification and beyond

“…Beyond the malignancy and other issues, recent years have seen much overall progress in meningioma genetics and molecular biology in general [ 63 ]. It appears that not all meningiomas are the same, and future meningioma classifications may be need to based at least in part on molecular and genetic parameters [ 29 , 48 , 65 ].…”

The Evolving Classification of Meningiomas: Integration of Molecular Discoveries to Inform Patient Care

“…Multiple large-cohort sequencing studies have established the landscape of somatic mutations in meningiomas, identifying mutually exclusive genomic subgroups that account for over 80% of all cases [9,66,96,97]. Bi-allelic loss of the tumor suppressor NF2 is associated with approximately one-half of sporadic meningiomas and most syndromic cases.…”