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.

Keywords: chromosome 22; genetic/molecular alteration; meningioma; signal pathways.

Figure 1. Schematic diagram illustrating the key elements of some of the most relevant signaling pathways involved in the pathogenesis of meningiomas

The Ras-Raf-MEK-MAPK/ERK, PI3K-Akt/PKB, PLCγ1-PKC, PLA2-COX, JAK-STAT3 and mTOR signaling pathways are represented in the upper part of the scheme, while the relationships between the pRb and p53 cell cycle associated signaling pathways are illustrated in the lower part of the scheme. The pathway scheme displayed was generated with the Ingenuity Pathway Analysis (IPA) software (Ingenuity Systems Inc., Redwood City, CA, USA).

Figure 2. Patterns of cytogenetic alterations proposed to reflect cytogenetic progression of meningiomas, according to Ketter et al

[79] (panel a), Weber et al. [25] (panel b), and Sayagues et al. [86] (panel c). Panel a, oncogenetic tree mixture model for the acquisition of chromosomal alterations in the development of meningiomas; the first two critical steps in the progression model correspond to monosomy 22, followed by loss of the short arm of chromosome 1. In the Weber et al model (panel b), progression from grade I to grade III is proposed to occur in parallel to the acquisition of specific chromosomal gains and losses at frequencies of more than 30% of cases; nevertheless, chromosomal changes may already have occurred in a lower grade in a smaller percentage of tumors. Finally, hypothetical intratumoral aneuploidization pathways defined on the basis of the patterns of clonal evolution observed for 11 chromosomes analyzed at the single cell level for individual tumors by Sayagues et al. (panel c).