Unveiling a Biomarker Signature of Meningioma: The Need for a Panel of Genomic, Epigenetic, Proteomic, and RNA Biomarkers to Advance Diagnosis and Prognosis

Abstract

Meningiomas are the most prevalent primary intracranial tumors. The majority are benign but can undergo dedifferentiation into advanced grades classified by World Health Organization (WHO) into Grades 1 to 3. Meningiomas' tremendous variability in tumor behavior and slow growth rates complicate their diagnosis and treatment. A deeper comprehension of the molecular pathways and cellular microenvironment factors implicated in meningioma survival and pathology is needed. This review summarizes the known genetic and epigenetic aberrations involved in meningiomas, with a focus on neurofibromatosis type 2 (NF2) and non-NF2 mutations. Novel potential biomarkers for meningioma diagnosis and prognosis are also discussed, including epigenetic-, RNA-, metabolomics-, and protein-based markers. Finally, the landscape of available meningioma-specific animal models is overviewed. Use of these animal models can enable planning of adjuvant treatment, potentially assisting in pre-operative and post-operative decision making. Discovery of novel biomarkers will allow, in combination with WHO grading, more precise meningioma grading, including meningioma identification, subtype determination, and prediction of metastasis, recurrence, and response to therapy. Moreover, these biomarkers may be exploited in the development of personalized targeted therapies that can distinguish between the 15 diverse meningioma subtypes.

Keywords: NF2 mutations; biomarker; meningioma; miRNA; proteomics.

Figure 1

Association between genetic/cytogenetic alteration, grade of meningiomas, and anatomical location of the meningioma. (A) shows the common locations of meningiomas in the central nervous system (CNS). Meningiomas arise in the meningeal layers of the brain or spinal cord. They are commonly seen in the parasagittal area, brain convexity, posterior fossa, skull base, and spine. (B) illustrates the common locations and gene mutations in meningiomas according to grade. Convexity meningiomas usually harbor NF2 and SMARCB1 mutations. Brain convexity harbors more Grades 2 and 3 meningiomas than skull base. Skull base meningiomas harbor mutations in AKT1, KLF4, TRAF7, SMO, PIK3CA, and POLR2A genes. Spinal cord meningiomas often harbor SMARCE1 mutations. Locations of Grade 3 meningiomas are highlighted in the right inset of panel (B). Grade 1 (benign) meningiomas commonly occur in the parasagittal and posterior fossa with alterations in chromosome 22 and variation in the second allele of neurofibromatosis 2 (NF2). Genetic alterations in AKT1, PIK3CA, SMO, TRAF7, KLF4, and SMARCB1 also take place in Grade 1 meningiomas in the presence or absence of NF2 mutations depending on the gene. Grade 2 (atypical) meningiomas tend to exist in the brain convexity and spine and can have a loss of a copy of chromosomes 1, 10, or 14 in addition to genetic alterations in NF2 and SMARCEl. Grade 3 (malignant or anaplastic) meningiomas are characterized by the absence of chromosome 9p and genetic alterations of NF2, BAP1, LDH229, CDKN2 A/B, and pTERT. BAP1 mutations are frequent rhabdoid meningioma subtype, rhabdoid meningiomas with BAP1 mutations are more aggressive compared to rhabdoid meningiomas devoid of these mutations [30].

Figure 2

NF2/Merlin signaling in a normal meningeal cell vs. Merlin-deficient meningioma cell. Merlin is an effective inhibitor of major signaling pathways that lead to cell proliferation, protein synthesis, and angiogenesis. In a normal meningeal arachnoid cap cell, the NF2 gene encodes for Merlin. Merlin is a cytoskeletal protein that interacts and complexes with integrin 3, receptor tyrosine kinases (RTKs), and β-catenin to inhibit mTOR signaling pathway, MAPK pathway, and WNT pathway, among others. Merlin inhibits downstream effectors of these pathways including RAS, PI3K, AKT, mTOR, and β-catenin. Additionally, Merlin interferes with the translocation of β-catenin into the nucleus, inhibiting canonical WNT signaling. Merlin also inhibits transcription factors YAP/TAZ and TEA by interacting with components of the Hippo pathway. Loss of Merlin function to NF2 mutations, such as in meningiomas, activates these pathways (indicated by arrows) and leads to cell proliferation, protein synthesis, and angiogenesis, contributing to meningioma incidence and progression.