51
views
0
recommends
+1 Recommend
0 collections
    0
    shares
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Genetic/molecular alterations of meningiomas and the signaling pathways targeted

      review-article

      Read this article at

      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          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.

          Related collections

          Most cited references100

          • Record: found
          • Abstract: found
          • Article: not found

          Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO.

          We report genomic analysis of 300 meningiomas, the most common primary brain tumors, leading to the discovery of mutations in TRAF7, a proapoptotic E3 ubiquitin ligase, in nearly one-fourth of all meningiomas. Mutations in TRAF7 commonly occurred with a recurrent mutation (K409Q) in KLF4, a transcription factor known for its role in inducing pluripotency, or with AKT1(E17K), a mutation known to activate the PI3K pathway. SMO mutations, which activate Hedgehog signaling, were identified in ~5% of non-NF2 mutant meningiomas. These non-NF2 meningiomas were clinically distinctive-nearly always benign, with chromosomal stability, and originating from the medial skull base. In contrast, meningiomas with mutant NF2 and/or chromosome 22 loss were more likely to be atypical, showing genomic instability, and localizing to the cerebral and cerebellar hemispheres. Collectively, these findings identify distinct meningioma subtypes, suggesting avenues for targeted therapeutics.
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations

            Meningiomas are the most common primary nervous system tumor. The tumor suppressor NF2 is disrupted in approximately half of meningiomas 1 but the complete spectrum of genetic changes remains undefined. We performed whole-genome or whole-exome sequencing on 17 meningiomas and focused sequencing on an additional 48 tumors to identify and validate somatic genetic alterations. Most meningiomas exhibited simple genomes, with fewer mutations, rearrangements, and copy-number alterations than reported in other adult tumors. However, several meningiomas harbored more complex patterns of copy-number changes and rearrangements including one tumor with chromothripsis. We confirmed focal NF2 inactivation in 43% of tumors and found alterations in epigenetic modifiers among an additional 8% of tumors. A subset of meningiomas lacking NF2 alterations harbored recurrent oncogenic mutations in AKT1 (E17K) and SMO (W535L) and exhibited immunohistochemical evidence of activation of their pathways. These mutations were present in therapeutically challenging tumors of the skull base and higher grade. These results begin to define the spectrum of genetic alterations in meningiomas and identify potential therapeutic targets.
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              Pathological classification and molecular genetics of meningiomas.

              Meningiomas are extremely common adult brain tumors originating from meningeal coverings of the brain and spinal cord. While most are slowly growing Word Health organization (WHO) grade I tumors, rare variants (clear cell, chordoid, papillary, and rhabdoid), as well as brain invasive (WHO grade II), atypical (WHO grade II), and anaplastic (WHO grade III) meningiomas are considerably more aggressive. This review summarizes the histopathological and genetic features of meningiomas, including differential diagnosis, pitfalls, and grading challenges. Early stages of meningioma tumorigenesis are closely linked to inactivation of one or more members of the 4.1 superfamily, including the neurofibromatosis type 2 (NF2) and 4.1B (DAL-1) genes, which interact with the 14-3-3 protein family. Other chromosome 22q genes implicated include BAM22, BCR (breakpoint cluster region), and TIMP-1, the last of which is implicated in higher-grade meningiomas. Atypical meningiomas also commonly show chromosomal losses of 1p, 6q, 10, 14q, and 18q, as well as multiple chromosomal gains. While most relevant genes remain unknown, two chromosome 14q candidates (MEG3 and NDRG2) have recently been identified. In addition to alterations of CDKN2A, p14(ARF), and CDKN2B tumor suppressor genes on 9p21, a contribution of the wingless (wnt) pathway with alterations of the E-cadherin and beta-catenin proteins, as well as alterations of the hedgehog signaling pathway have been implicated in anaplastic meningiomas. The integration of histopathological appearance, complex genetic/genomic data, and outcome will likely result in the identification of clinically distinct meningioma subgroups, which in turn can facilitate the development of targeted therapeutic strategies.
                Bookmark

                Author and article information

                Journal
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                10 May 2015
                19 April 2015
                : 6
                : 13
                : 10671-10688
                Affiliations
                1 Centre for Neurosciences and Cell Biology and Faculty of Pharmacy, University of Coimbra, Coimbra, Portugal
                2 Centre for Cancer Research (CIC-IBMCC, CSIC/USAL, IBSAL) and Department of Medicine, University of Salamanca, Salamanca, Spain
                3 Neurosurgery Service, University Hospital of Salamanca, Salamanca, Spain
                4 Instituto de Estudios de Ciencias de la salud de Castilla y León (IECSCYL-IBSAL) and Research Unit of the University Hospital of Salamanca, Salamanca, Spain
                Author notes
                Correspondence to: María Dolores Tabernero, taberner@ 123456usal.es
                Article
                10.18632/oncotarget.3870
                4484411
                25965831
                6abea19b-c721-4213-a193-1e4857fe2315
                Copyright: © 2015 Domingues et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 9 March 2015
                : 4 April 2015
                Categories
                Review

                Oncology & Radiotherapy
                genetic/molecular alteration,signal pathways,meningioma,chromosome 22
                Oncology & Radiotherapy
                genetic/molecular alteration, signal pathways, meningioma, chromosome 22

                Comments

                Comment on this article