Genetic/molecular alterations of meningiomas and the signaling pathways targeted

Abstract

Meningiomas are usually considered to be benign central nervous system tumors; however, they show heterogenous clinical, histolopathological and cytogenetic features associated with a variable outcome. In recent years important advances have been achieved in the identification of the genetic/molecular alterations of meningiomas and the signaling pathways involved. Thus, monosomy 22, which is often associated with mutations of the NF2 gene, has emerged as the most frequent alteration of meningiomas; in addition, several other genes (e.g. AKT1, KLF4, TRAF7, SMO) and chromosomes have been found to be recurrently altered often in association with more complex karyotypes and involvement of multiple signaling pathways. Here we review the current knowledge about the most relevant genes involved and the signaling pathways targeted by such alterations. In addition, we summarize those proposals that have been made so far for classification and prognostic stratification of meningiomas based on their genetic/genomic features.

Global epigenetic profiling identifies methylation subgroups associated with recurrence-free survival in meningioma

“…The most common cytogenetic alteration, 22q loss, is observed across WHO grades, whereas losses of chromosomes 1p, 6q, 10, 14q, 18q and gains of chromosomes 1q, 9q, 12q, 15q, 17q, 20q enrich the WHO grade II and III tumors [76,45,39,16,60,75]. Chromosome 9p loss is frequently associated with anaplastic astrocytomas [61,75].…”

“…The most commonly activated signaling and metabolic canonical pathways described in meningiomas are the RB/p53 pathway, MAPK and PI3K/AKT, PLCγ/PKC-calcium signaling pathway, the cyclooxygenase-2 signaling pathway, mTOR, WNT/β-catenin, Notch, and Hedgehog signaling pathways [16,33,32,50]. This is overall in keeping with our findings (Online resource 7), noting that comparative pathway analysis identified a stronger activation of the WNT/β-catenin signaling pathway in the MA subgroup opposing the activation of retinoate biosynthesis and leukocyte extravasation signaling in the MB subgroup (Online resource 8)…”

“…Although numerous molecular alterations have been described in meningioma [62,10,13,65,1,16,9] few of which were linked to prognosis, like 1p36 loss [39,45], 9p21 loss [61], complex karyotypes [17,45], and recently TERT promoter mutations [65], these alterations are not yet integrated with the morphological diagnosis in the most recent, revised WHO classification [41] and molecular testing is not routinely performed in the clinic for patients with meningioma. Meningioma recurrence may warrant adjuvant radiation therapy or increased monitoring [54] but these patients are not accurately identified by the current meningioma classification system.…”

Update on Select Benign Mesenchymal and Meningothelial Sinonasal Tract Lesions

“…Abnormalities in genes on chromosomes 1p, 6, 9p, 10q, 14q, 17p, 18q and 22 have been described, [77,84,87,88] with deletions of chromosome 22 (monosomy 22) the most consistent cytogenetic alteration. Specifically, these include mutations of the NF2 gene (chromosome 22q12.2), which codes for the protein merlin, a tumor suppressor gene.…”

“…Merlin is lost in different meningioma types, while Yes-associated protein (YAP) is increased, resulting in meningioma proliferation [89]. Loss of 1p is the second most common chromosomal abnormality, correlated to ELAVL4 gene which reveals a distinct gender difference [90], and to ALPL (1p36.1-p34) which is down regulated, associated with high grade tumors and recurrence [88]. Several other genes and chromosomes have been elucidated in meningioma, but tend to be associated with Grade II and III tumors or with tumor progression, features not normally present in the sinonasal tract [77,84,87,91].…”