Familial Syndromes Involving Meningiomas Provide Mechanistic Insight Into Sporadic Disease

Familial Syndromes Involving Meningiomas Provide Mechanistic Insight Into Sporadic Disease Abstract Currently, there is an incomplete understanding of the molecular pathogenesis of meningiomas, the most common primary brain tumor. Several familial syndromes are characterized by increased meningioma risk, and the genetics of these syndromes provides mechanistic insight into sporadic disease. The best defined of these syndromes is neurofibromatosis type 2, which is caused by a mutation in the NF2 gene and has a meningioma incidence of approximately 50%. This finding led to the subsequent discovery that NF2 loss-of-function occurs in up to 60% of sporadic tumors. Other important familial diseases with increased meningioma risk include nevoid basal cell carcinoma syndrome, multiple endocrine neoplasia 1 (MEN1), Cowden syndrome, Werner syndrome, BAP1 tumor predisposition syndrome, Rubinstein-Taybi syndrome, and familial meningiomatosis caused by germline mutations in the SMARCB1 and SMARCE1 genes. For each of these syndromes, the diagnostic criteria, incidence in the population, and frequency of meningioma are presented to review the relevant clinical information for these conditions. The genetic mutations, molecular pathway derangements, and relationship to sporadic disease for each syndrome are described in detail to identify targets for further investigation. Familial syndromes characterized by meningiomas often affect genes and pathways that are also implicated in a subset of sporadic cases, suggesting key molecular targets for therapeutic intervention. Further studies are needed to resolve the functional relevance of specific genes whose significance in sporadic disease remains to be elucidated. Familial meningioma, Meningioma, Meningioma genetics, Meningioma pathogenesis ABBREVIATIONS ABBREVIATIONS AKT1 v-Akt murine thymoma viral oncogene homolog 1 BCC basal cell carcinoma CS Cowden syndrome IHC immunohistochemistry KLF4 Kruppel-like factor 4 MBAIT melanocytic BAP1-mutated atypical intradermal tumors MEN1 multiple endocrine neoplasia 1 NBCCS nevoid basal cell carcinoma syndrome NF2 neurofibromatosis type 2 PHTS PTEN hamartoma tumor syndrome PI3K phosphatidylinositol 3-kinase PTEN phosphatase and tensin homolog SHH sonic hedgehog SMO smoothened TRAF7 TNF receptor-associated factor 7 Meningiomas are the most common primary brain tumor reported in the United States, comprising approximately 36% of brain tumors.1,2 Estimates from recent data predict that more than 20 000 new meningiomas will be diagnosed each year, with an incidence of 7.5 per 100 000.2 While the majority of these tumors are sporadic, there are many familial syndromes that place a patient at increased risk for meningioma development. The most well characterized and documented of these genetic syndromes is neurofibromatosis type 2 (NF2). Identification of the NF2 gene led to the investigation of molecular genetic mutations in sporadic meningiomas, in which up to 60% of patients have also been found to have somatic inactivation of NF2.3,4 Recent whole genome sequencing and whole exome sequencing studies in non-NF2 mutated meningiomas have further delineated additional mutations in TRAF7, KLF4, AKT1, PI3K, and SMO; however, many sporadic tumors still have not been found to have a genetic basis (Figure 1).5,6 Greater understanding of the familial syndromes associated with meningiomatosis may elucidate further molecular mechanisms behind the development of sporadic meningiomas. Below, we present a review of familial syndromes associated with meningioma predisposition. FIGURE 1. View largeDownload slide Locations of known mutations in meningioma. Loss of chromosome regions shown in black, gain of chromosome regions shown in red. FIGURE 1. View largeDownload slide Locations of known mutations in meningioma. Loss of chromosome regions shown in black, gain of chromosome regions shown in red. METHODS A review of the PubMed database was conducted to identify published studies on known familial meningioma syndromes up until June 2017. Combinations of search terms used included “meningioma,” “familial meningiomatosis,” “familial meningioma,” “nevoid basal cell carcinoma syndrome,” “Gorlin syndrome,” “multiple endocrine neoplasia 1,” “Cowden syndrome,” “Werner syndrome,” “BAP1 tumor predisposition syndrome,” “SMARCB1,” “SMARCE1,” “SUFU,” and “Rubinstein-Taybi syndrome.” Only studies available in English were included. All identified abstracts from these searches were analyzed, and those that reviewed or examined familial syndromes associated with meningiomas were included. RESULTS A review of PubMed abstracts from the described search criteria resulted in 46 studies that met inclusion (see Supplemental Digital Content). The results from these studies are presented below and include NF2, nevoid basal cell carcinoma syndrome (NBCCS, also known as Gorlin syndrome), multiple endocrine neoplasia 1 (MEN1), Cowden syndrome (CS), Werner syndrome, BAP1 tumor predisposition syndrome, Rubinstein-Taybi syndrome, and familial meningiomatosis caused by germline mutations in the SMARCB1 and SMARCE1 genes (Table 1). TABLE 1. List of Syndromes, Mutations, Pathways, and Sporadic Relationships Syndrome  Mutated gene  Involved pathway  Relationship to sporadic tumors  NF2  NF2 tumor suppressor  EGFR, YAP/TAZ, MAPK, cytoskeletal architecture  Mutated in 40%-60%  Werner  WRN  DNA processing, maintenance and repair  Methylated with decrease in expression  BAP1-TPDS  BAP1  Chromatin Remodeling, DNA repair  Found in high-grade rhabdoid meningiomas  SMARCE1  SMARCE1  Nucleosome remodeling, apoptosis  Found in Clear cell meningiomas  SMARCB1  SMARCB1  Nucleosome remodeling, apoptosis  Mutated in 3%  Gorlin  PTCH1  SHH – PTCH1/SMO/SUFU/GLI-1,2,3  SMO mutated in 5%  Cowden  PTEN  PI3K – RTK/AKT/PI3K/mTOR/PTEN  AKT mutated in 14%; PIK3CA mutated in 7%  Syndrome  Mutated gene  Involved pathway  Relationship to sporadic tumors  NF2  NF2 tumor suppressor  EGFR, YAP/TAZ, MAPK, cytoskeletal architecture  Mutated in 40%-60%  Werner  WRN  DNA processing, maintenance and repair  Methylated with decrease in expression  BAP1-TPDS  BAP1  Chromatin Remodeling, DNA repair  Found in high-grade rhabdoid meningiomas  SMARCE1  SMARCE1  Nucleosome remodeling, apoptosis  Found in Clear cell meningiomas  SMARCB1  SMARCB1  Nucleosome remodeling, apoptosis  Mutated in 3%  Gorlin  PTCH1  SHH – PTCH1/SMO/SUFU/GLI-1,2,3  SMO mutated in 5%  Cowden  PTEN  PI3K – RTK/AKT/PI3K/mTOR/PTEN  AKT mutated in 14%; PIK3CA mutated in 7%  View Large TABLE 1. List of Syndromes, Mutations, Pathways, and Sporadic Relationships Syndrome  Mutated gene  Involved pathway  Relationship to sporadic tumors  NF2  NF2 tumor suppressor  EGFR, YAP/TAZ, MAPK, cytoskeletal architecture  Mutated in 40%-60%  Werner  WRN  DNA processing, maintenance and repair  Methylated with decrease in expression  BAP1-TPDS  BAP1  Chromatin Remodeling, DNA repair  Found in high-grade rhabdoid meningiomas  SMARCE1  SMARCE1  Nucleosome remodeling, apoptosis  Found in Clear cell meningiomas  SMARCB1  SMARCB1  Nucleosome remodeling, apoptosis  Mutated in 3%  Gorlin  PTCH1  SHH – PTCH1/SMO/SUFU/GLI-1,2,3  SMO mutated in 5%  Cowden  PTEN  PI3K – RTK/AKT/PI3K/mTOR/PTEN  AKT mutated in 14%; PIK3CA mutated in 7%  Syndrome  Mutated gene  Involved pathway  Relationship to sporadic tumors  NF2  NF2 tumor suppressor  EGFR, YAP/TAZ, MAPK, cytoskeletal architecture  Mutated in 40%-60%  Werner  WRN  DNA processing, maintenance and repair  Methylated with decrease in expression  BAP1-TPDS  BAP1  Chromatin Remodeling, DNA repair  Found in high-grade rhabdoid meningiomas  SMARCE1  SMARCE1  Nucleosome remodeling, apoptosis  Found in Clear cell meningiomas  SMARCB1  SMARCB1  Nucleosome remodeling, apoptosis  Mutated in 3%  Gorlin  PTCH1  SHH – PTCH1/SMO/SUFU/GLI-1,2,3  SMO mutated in 5%  Cowden  PTEN  PI3K – RTK/AKT/PI3K/mTOR/PTEN  AKT mutated in 14%; PIK3CA mutated in 7%  View Large Neurofibromatosis Type 2 NF2 is an autosomal dominant, 100% penetrant condition characterized by a constellation of schwannomas and meningiomas.7 NF2 is clinically diagnosed using the Manchester criteria, the details of which are in Table 2. The overall prevalence of NF2 in the population is approximately 1 in 60 000.8 TABLE 2. Neurofibromatosis Type 2 Diagnostic Criteria   A diagnosis can be made if an individual meets one of the following:    Bilateral vestibular schwannomas    A first degree relative with NF2 + unilateral vestibular schwannoma or 2 NF2-associated lesions*    Unilateral vestibular schwannoma + 2 NF2-associated lesions*    Multiple meningiomas + unilateral vestibular schwannoma or 2 other NF-2 associated lesions*    A diagnosis can be made if an individual meets one of the following:    Bilateral vestibular schwannomas    A first degree relative with NF2 + unilateral vestibular schwannoma or 2 NF2-associated lesions*    Unilateral vestibular schwannoma + 2 NF2-associated lesions*    Multiple meningiomas + unilateral vestibular schwannoma or 2 other NF-2 associated lesions*  *Meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities. View Large TABLE 2. Neurofibromatosis Type 2 Diagnostic Criteria   A diagnosis can be made if an individual meets one of the following:    Bilateral vestibular schwannomas    A first degree relative with NF2 + unilateral vestibular schwannoma or 2 NF2-associated lesions*    Unilateral vestibular schwannoma + 2 NF2-associated lesions*    Multiple meningiomas + unilateral vestibular schwannoma or 2 other NF-2 associated lesions*    A diagnosis can be made if an individual meets one of the following:    Bilateral vestibular schwannomas    A first degree relative with NF2 + unilateral vestibular schwannoma or 2 NF2-associated lesions*    Unilateral vestibular schwannoma + 2 NF2-associated lesions*    Multiple meningiomas + unilateral vestibular schwannoma or 2 other NF-2 associated lesions*  *Meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities. View Large NF2 is caused by germline mutations in the NF2 tumor suppressor gene, located at 22q12.2. The protein product is called merlin or schwannomin.9 Within the cell, merlin has been found to interact with several proteins that affect PI3K, YAP/TAZ, and mitogen-activated protein kinase (MAPK) signaling. All 3 pathways are important in cell growth and cellular proliferation.8,10,11 Given its location at the cell membrane-cytoskeletal interface, several other potential functions have been proposed, including contact-dependent inhibition of EGFR, effects on cell-to-cell adhesion, and regulation of cytoskeletal architecture.12-14 The role of NF2 inactivation in sporadic meningiomas was investigated due to the high frequency of meningiomas in NF2 patients. The frequency of NF2 inactivation is estimated to be present between in 40% and 60% of cases of sporadic meningiomas based on several studies, and this mutation is thought to be the causative mutation in these cases.4 Interestingly, NF2-mutated meningiomas have certain location predilections.5 Those with NF2 mutations and/or chromosome 22 loss were found preferentially in the hemispheres. For meningiomas of the skull base, those located laterally and posteriorly were significantly more likely to have NF2 mutations and/or chromosome 22 loss, whereas medially located skull base tumors were more commonly non-NF2 mutated. The work on NF2 has provided an excellent example of how investigating a familial syndrome with meningiomas can lead to establishing the genetic basis for sporadic disease. Nevoid Basal Cell Carcinoma Syndrome Nevoid basal cell carcinoma syndrome, also known as basal cell nevus syndrome or Gorlin syndrome, is an autosomal dominant syndrome that is classically characterized by multiple basal cell carcinomas (BCC), jaw keratocysts, and bifid ribs.15 The complete list of major clinical criteria required for diagnosis and cited by several studies is detailed in Table 3. 16,20 The estimated prevalence is between 1 in 30 000 and 1 in 256 000 and equally affects men and women.16,17 Additional tumors that are associated with the syndrome include meningiomas and rhabdomyosarcomas.16,18 TABLE 3. Nevoid Basal Cell Carcinoma Syndrome Diagnostic Criteria   A diagnosis can be made if an individual meets 2 major criteria or 1 major + 2 minor criteria  Major criteria  Minor criteria  Basal cell carcinomas: ≥5 in a lifetime or 1 diagnosed before age 30  Childhood medulloblastoma  Lamellar calcification of the falx before the age of 20  Lympho-mesenteric or pleural cysts  Jaw odontogenic keratocyst  Macrocephaly (occipitofrontal circumference (OFC) > 97th percentile)  Palmar or plantar pits: ≥2  Cleft lip/palate  First-degree relative with NBCCS  Vertebral or rib anomalies (bifid/splayed/extra ribs, bifid vertebrae)    Preaxial or postaxial polydactyly    Ovarian or cardiac fibromas    Ocular anomalies (cataract, developmental defects, pigmentary changes of the retinal epithelium)    A diagnosis can be made if an individual meets 2 major criteria or 1 major + 2 minor criteria  Major criteria  Minor criteria  Basal cell carcinomas: ≥5 in a lifetime or 1 diagnosed before age 30  Childhood medulloblastoma  Lamellar calcification of the falx before the age of 20  Lympho-mesenteric or pleural cysts  Jaw odontogenic keratocyst  Macrocephaly (occipitofrontal circumference (OFC) > 97th percentile)  Palmar or plantar pits: ≥2  Cleft lip/palate  First-degree relative with NBCCS  Vertebral or rib anomalies (bifid/splayed/extra ribs, bifid vertebrae)    Preaxial or postaxial polydactyly    Ovarian or cardiac fibromas    Ocular anomalies (cataract, developmental defects, pigmentary changes of the retinal epithelium)  View Large TABLE 3. Nevoid Basal Cell Carcinoma Syndrome Diagnostic Criteria   A diagnosis can be made if an individual meets 2 major criteria or 1 major + 2 minor criteria  Major criteria  Minor criteria  Basal cell carcinomas: ≥5 in a lifetime or 1 diagnosed before age 30  Childhood medulloblastoma  Lamellar calcification of the falx before the age of 20  Lympho-mesenteric or pleural cysts  Jaw odontogenic keratocyst  Macrocephaly (occipitofrontal circumference (OFC) > 97th percentile)  Palmar or plantar pits: ≥2  Cleft lip/palate  First-degree relative with NBCCS  Vertebral or rib anomalies (bifid/splayed/extra ribs, bifid vertebrae)    Preaxial or postaxial polydactyly    Ovarian or cardiac fibromas    Ocular anomalies (cataract, developmental defects, pigmentary changes of the retinal epithelium)    A diagnosis can be made if an individual meets 2 major criteria or 1 major + 2 minor criteria  Major criteria  Minor criteria  Basal cell carcinomas: ≥5 in a lifetime or 1 diagnosed before age 30  Childhood medulloblastoma  Lamellar calcification of the falx before the age of 20  Lympho-mesenteric or pleural cysts  Jaw odontogenic keratocyst  Macrocephaly (occipitofrontal circumference (OFC) > 97th percentile)  Palmar or plantar pits: ≥2  Cleft lip/palate  First-degree relative with NBCCS  Vertebral or rib anomalies (bifid/splayed/extra ribs, bifid vertebrae)    Preaxial or postaxial polydactyly    Ovarian or cardiac fibromas    Ocular anomalies (cataract, developmental defects, pigmentary changes of the retinal epithelium)  View Large Specifically, meningiomas were reported in 5% of NBCCS patients in 2 studies.19,20 Given that meningiomas commonly arise from the falx cerebri, it is interesting to note that NBCCS is characterized by prominent calcifications of this area.16,19 The genetic causes behind NBCCS are pathogenic mutations in genes of the sonic hedgehog (SHH) signaling pathway including PTCH1, PTCH2, and SUFU, located at 9q22.32, 1p34.1, and 10q24.32, respectively, with variations in PTCH1 being the most common.21,22 The activation of this pathway drives cell proliferation in both normal neural development and in tumor development.23 In BCC and a subset of medulloblastoma, the loss of PTCH1 or SUFU and the activation of SMO have been implicated in tumor initiation and maintenance.24,25 In fact, mutations in PTCH1 or SMO are sufficient to drive tumorigenesis in BCC and medulloblastoma mouse models.23,26,27 The PTCH1 gene codes for a protein that constitutes the ligand-binding component of the SHH receptor complex. The details of the SHH pathway are depicted in Figure 2.28,29 FIGURE 2. View largeDownload slide Details of the SHH and Akt pathways. Without SHH binding, PTCH1 renders smoothened (SMO) inactive and inhibits it from signaling downstream targets. When SHH binds to PTCH1, SMO is released from this inhibition, allowing it to interact with SUFU. This results in the activation and nuclear translocation of glioma-associated oncogene homologue 1 (GLI1) and (GLI2), and the degradation of GLI3. In the Akt pathway, PTEN normally targets IP3 to inhibit the phosphorylation of Akt. When growth factor (GF) binding to receptor tyrosine kinases (RTK) occurs, PI3K signaling is increased, leading to IP3 accumulation, phosphorylation of Akt and activation of downstream targets. FIGURE 2. View largeDownload slide Details of the SHH and Akt pathways. Without SHH binding, PTCH1 renders smoothened (SMO) inactive and inhibits it from signaling downstream targets. When SHH binds to PTCH1, SMO is released from this inhibition, allowing it to interact with SUFU. This results in the activation and nuclear translocation of glioma-associated oncogene homologue 1 (GLI1) and (GLI2), and the degradation of GLI3. In the Akt pathway, PTEN normally targets IP3 to inhibit the phosphorylation of Akt. When growth factor (GF) binding to receptor tyrosine kinases (RTK) occurs, PI3K signaling is increased, leading to IP3 accumulation, phosphorylation of Akt and activation of downstream targets. A meningioma has been reported in a patient with NBCCS with a confirmed germline PTCH1 mutation in which the genetic sequencing of the patient's meningioma revealed an additional somatic mutation in PTCH1. Using the Knudson's 2-hit theory, they considered the development of this meningioma to be caused by loss of function of PTCH1.30 Additionally, driver mutations in SMO have been identified as one of the most common non-NF2 mutations in sporadic meningiomas, and have a predilection for the olfactory groove. Meningiomas with an SMO mutation in the olfactory groove have been found to have a higher recurrence rate, especially late recurrences (>5 yr). Given this information and the significance with regard to prognostication, surgeons and neuro-oncologists should consider testing olfactory groove meningiomas specifically for SMO mutations and adjusting their follow-up schedule accordingly for these lesions, which is currently commercially available at multiple CLIA (Clinical Laboratory Improvement Amendments)-certified laboratories.5,31 Patients with NBCCS caused by SUFU mutations have been found to be significantly more likely to have a meningioma in comparison to NBCCS patients caused by PTCH1 or PTCH2 mutations.22SUFU mutations have also been investigated in a family with multiple meningiomas and the absence of other features of NBCCS.32 Genome-wide linkage analysis and exome sequencing in this family found that germline SUFU mutations segregated with disease in the family. Functional studies showed that the identified mutation led to significantly increased SHH pathway activation due to loss of the normal suppressor function of SUFU. This group also sequenced the coding exons and exon-intron boundaries of SUFU in blood/germline samples of 162 meningiomas (11 of these patients had a familial history of meningiomas and 40 had multiple meningiomas) from a national meningioma database; however, no pathogenic variants of SUFU were detected. The SHH pathway is critical to the formation of meningiomas in some instances. Studies on patients with NBCCS and familial meningiomatosis due to germline SUFU mutations have provided important information into the mechanisms by which derangement of the SHH pathway can lead to these tumors. Further research into the other components of this pathway is important. Cowden Syndrome Cowden syndrome, part of the PTEN hamartoma tumor syndrome (PHTS), is an autosomal dominant disorder caused by germline mutations in phosphatase and tensin homolog (PTEN) on chromosome 10q23.31.33 Its diagnostic criteria include a host of major and minor criteria as well as pathognomonic findings listed in Table 4.34 CS is estimated to affect between 1 in 200 000 and 1 in 250 000 people.35,36 Although not part of the major or minor criteria, meningiomas are found in approximately 8% of patients.37 Other clinical syndromes that are classified as PHTS include Bannayan-Riley-Ruvalcaba and Proteus syndrome.33 Multiple case reports have also identified meningiomas in patients with Proteus syndrome.38,39 TABLE 4. Cowden Syndrome Diagnostic Criteria   A diagnosis can be made if an individual meets 3 major criteria (1 must be macrocephaly, LDD, or GI hamartomas) or 2 major + 3 minor criteria*  Major criteria  Minor criteria  Breast cancer  Autism spectrum disorder  Endometrial cancer (epithelial)  Colon cancer  Thyroid cancer (follicular)  Esophageal glycogenic acanthosis: ≥ 3  Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps): ≥ 3  Lipomas: ≥ 3  Adult Lhermitte-Duclos disease (LDD)  Intellectual disability (IQ ≤ 75)  Macrocephaly (occipitofrontal circumference (OFC) ≥ 97th percentile)  Renal cell carcinoma  Macular pigmentation of the glans penis  Testicular lipomatosis  Multiple mucocutaneous lesions (any of the following):  Thyroid cancer (papillary or follicular variant of papillary)  Trichilemmomas: ≥ 3, at least one biopsy proven  Thyroid lesions (adenoma, multinodular goiter)  Acral keratoses: ≥ 3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)  Vascular anomalies (including multiple intracranial developmental venous anomalies)  Mucocutaneous neuromas: ≥ 3    Oral papillomas (particularly on tongue and gingiva): ≥ 3 or 1 biopsy proven/dermatologist diagnosed      A diagnosis can be made if an individual meets 3 major criteria (1 must be macrocephaly, LDD, or GI hamartomas) or 2 major + 3 minor criteria*  Major criteria  Minor criteria  Breast cancer  Autism spectrum disorder  Endometrial cancer (epithelial)  Colon cancer  Thyroid cancer (follicular)  Esophageal glycogenic acanthosis: ≥ 3  Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps): ≥ 3  Lipomas: ≥ 3  Adult Lhermitte-Duclos disease (LDD)  Intellectual disability (IQ ≤ 75)  Macrocephaly (occipitofrontal circumference (OFC) ≥ 97th percentile)  Renal cell carcinoma  Macular pigmentation of the glans penis  Testicular lipomatosis  Multiple mucocutaneous lesions (any of the following):  Thyroid cancer (papillary or follicular variant of papillary)  Trichilemmomas: ≥ 3, at least one biopsy proven  Thyroid lesions (adenoma, multinodular goiter)  Acral keratoses: ≥ 3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)  Vascular anomalies (including multiple intracranial developmental venous anomalies)  Mucocutaneous neuromas: ≥ 3    Oral papillomas (particularly on tongue and gingiva): ≥ 3 or 1 biopsy proven/dermatologist diagnosed    *In an individual who has a relative who meets the above criteria or has a PTEN mutation, a diagnosis can be made if he or she meets 2 major criteria, 1 major + 2 minor criteria, or 3 minor criteria. View Large TABLE 4. Cowden Syndrome Diagnostic Criteria   A diagnosis can be made if an individual meets 3 major criteria (1 must be macrocephaly, LDD, or GI hamartomas) or 2 major + 3 minor criteria*  Major criteria  Minor criteria  Breast cancer  Autism spectrum disorder  Endometrial cancer (epithelial)  Colon cancer  Thyroid cancer (follicular)  Esophageal glycogenic acanthosis: ≥ 3  Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps): ≥ 3  Lipomas: ≥ 3  Adult Lhermitte-Duclos disease (LDD)  Intellectual disability (IQ ≤ 75)  Macrocephaly (occipitofrontal circumference (OFC) ≥ 97th percentile)  Renal cell carcinoma  Macular pigmentation of the glans penis  Testicular lipomatosis  Multiple mucocutaneous lesions (any of the following):  Thyroid cancer (papillary or follicular variant of papillary)  Trichilemmomas: ≥ 3, at least one biopsy proven  Thyroid lesions (adenoma, multinodular goiter)  Acral keratoses: ≥ 3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)  Vascular anomalies (including multiple intracranial developmental venous anomalies)  Mucocutaneous neuromas: ≥ 3    Oral papillomas (particularly on tongue and gingiva): ≥ 3 or 1 biopsy proven/dermatologist diagnosed      A diagnosis can be made if an individual meets 3 major criteria (1 must be macrocephaly, LDD, or GI hamartomas) or 2 major + 3 minor criteria*  Major criteria  Minor criteria  Breast cancer  Autism spectrum disorder  Endometrial cancer (epithelial)  Colon cancer  Thyroid cancer (follicular)  Esophageal glycogenic acanthosis: ≥ 3  Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps): ≥ 3  Lipomas: ≥ 3  Adult Lhermitte-Duclos disease (LDD)  Intellectual disability (IQ ≤ 75)  Macrocephaly (occipitofrontal circumference (OFC) ≥ 97th percentile)  Renal cell carcinoma  Macular pigmentation of the glans penis  Testicular lipomatosis  Multiple mucocutaneous lesions (any of the following):  Thyroid cancer (papillary or follicular variant of papillary)  Trichilemmomas: ≥ 3, at least one biopsy proven  Thyroid lesions (adenoma, multinodular goiter)  Acral keratoses: ≥ 3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)  Vascular anomalies (including multiple intracranial developmental venous anomalies)  Mucocutaneous neuromas: ≥ 3    Oral papillomas (particularly on tongue and gingiva): ≥ 3 or 1 biopsy proven/dermatologist diagnosed    *In an individual who has a relative who meets the above criteria or has a PTEN mutation, a diagnosis can be made if he or she meets 2 major criteria, 1 major + 2 minor criteria, or 3 minor criteria. View Large The PTEN protein acts as a phosphatase to dephosphorylate various cellular lipids and proteins. Dysfunctional PTEN leads to upregulation of the PI3K-AKT-mTOR (mammalian target of rapamycin) pathway, resulting in increases in cell proliferation, energy metabolism, and survival.40 It has been found to be important in breast and prostate cancer as well as glioblastoma multiforme.41 In mouse models of glioma, PTEN deletion results in earlier tumor onset and increases tumor grade.42,43 PTEN targets include phosphatidylinositol trisphosphate and phosphatidylinositol bisphosphate, both products of PI3K. This pathway is illustrated in Figure 2. As part of its protein phosphatase activity, PTEN has been shown to dephosphorylate focal adhesion kinase, which has negative effects on cell migration and cell spreading, as well as MAPK that regulates cell survival.44,45 In sporadic meningiomas, higher-grade tumors are associated with progressive changes at the chromosomal level including losses of chromosomes 1p, 9q, 10q, 14q, and 22q.46 Given this information and PTEN’s location at 10q23.3, it was investigated as a candidate gene in sporadic meningiomas.47 Using a group of 55 WHO grade I, 10 grade II, and 10 grade III meningiomas, Peters et al47 sequenced the entire coding sequence of the PTEN gene in tumor samples. No PTEN mutations were seen in the grade I tumors, but 1 grade III tumor harbored a somatic mutation in PTEN. These findings led them to hypothesize that mutations in PTEN are unlikely to be involved in the initiation and formation of low-grade meningiomas, but may contribute to malignant progression to higher-grade lesions. Such a conclusion supports other work in the chromosomal analysis comparing high-grade and low-grade sporadic meningiomas.46 This is similar to gliomas in that low-grade gliomas do not have as high of a frequency of PTEN loss as high-grade gliomas.48 Given PTEN’s role in regulation of the PI3K-AKT-mTOR pathway, and evidence of dysregulation of this pathway in many cancers, downstream targets of PTEN have also been investigated as potential oncogenic drivers in meningioma.49 Both AKT and PI3KA mutations have been found in sporadic meningiomas, comprising approximately 9% and 7% of non-NF2-mutant meningiomas, respectively.5,50 The complexity of this pathway suggests ample room for more investigation into the role of both PTEN and its downstream targets in meningioma pathogenesis. Previous research in patients with CS has provided some of the framework for our understanding of this pathway's role in cancer. Werner Syndrome Werner syndrome, also known as adult progeria, was first described in a set of siblings with short stature, “senile” appearance, premature graying of the hair, early-onset cataracts, dermatologic changes, and muscle atrophy.51 Biallelic mutations in the WRN gene (also known as RECQL2) were later established as the cause of the syndrome, which is inherited in an autosomal recessive manner.52 A set of cardinal and additional signs and symptoms has been designated and was updated most recently in 2013 (Table 5).53 A definite diagnosis is achieved when all 6 cardinal signs are present or a gene mutation and at least 3 cardinal signs are present. Interestingly, Japan has the highest frequency of carriers, at rates of 6 per 1000, while the disease prevalence in the overall population is estimated to be 1 in 1000 000 individuals based on publically available allele frequency databases.54,55 A patient with Werner syndrome is approximately 36.2 times Standardized Incidence Ratio (SIR); 95% confidence interval 17.3, 66.5) more likely to develop a meningioma than the general population and are more likely to develop them at a younger age.56 In addition, the proportion of meningiomas to other brain tumors in the Werner Syndrome is higher than expected.57 TABLE 5. Werner Syndrome Diagnostic Criteria   A confirmed diagnosis can be made if an individual has all 6 cardinal signs or a WRN mutation + 3 cardinal signs. A diagnosis is suspected if an individual has 2 cardinal signs or 1 cardinal sign + additional signs  Cardinal signs*  Additional signs  Premature greying or thinning of scalp hair  Abnormal glucose and/or lipid metabolism  Bilateral cataracts  Skeletal abnormalities (osteoporosis)  Characteristic dermatologic changes (atrophic skin, tight skin, clavus, callus, intractable skin ulcers)  Malignant tumors (nonepithelial tumors, thyroid cancer)  Soft-tissue calcification (Achilles tendon)  Parental consanguinity  ‘Bird-like’ facies  Premature atherosclerosis (angina pectoris, myocardial infarction)  Abnormal voice (high pitched, squeaky, hoarse)  Hypogonadism    Short stature and low bodyweight    A confirmed diagnosis can be made if an individual has all 6 cardinal signs or a WRN mutation + 3 cardinal signs. A diagnosis is suspected if an individual has 2 cardinal signs or 1 cardinal sign + additional signs  Cardinal signs*  Additional signs  Premature greying or thinning of scalp hair  Abnormal glucose and/or lipid metabolism  Bilateral cataracts  Skeletal abnormalities (osteoporosis)  Characteristic dermatologic changes (atrophic skin, tight skin, clavus, callus, intractable skin ulcers)  Malignant tumors (nonepithelial tumors, thyroid cancer)  Soft-tissue calcification (Achilles tendon)  Parental consanguinity  ‘Bird-like’ facies  Premature atherosclerosis (angina pectoris, myocardial infarction)  Abnormal voice (high pitched, squeaky, hoarse)  Hypogonadism    Short stature and low bodyweight  *Age of onset between 10-40 years. View Large TABLE 5. Werner Syndrome Diagnostic Criteria   A confirmed diagnosis can be made if an individual has all 6 cardinal signs or a WRN mutation + 3 cardinal signs. A diagnosis is suspected if an individual has 2 cardinal signs or 1 cardinal sign + additional signs  Cardinal signs*  Additional signs  Premature greying or thinning of scalp hair  Abnormal glucose and/or lipid metabolism  Bilateral cataracts  Skeletal abnormalities (osteoporosis)  Characteristic dermatologic changes (atrophic skin, tight skin, clavus, callus, intractable skin ulcers)  Malignant tumors (nonepithelial tumors, thyroid cancer)  Soft-tissue calcification (Achilles tendon)  Parental consanguinity  ‘Bird-like’ facies  Premature atherosclerosis (angina pectoris, myocardial infarction)  Abnormal voice (high pitched, squeaky, hoarse)  Hypogonadism    Short stature and low bodyweight    A confirmed diagnosis can be made if an individual has all 6 cardinal signs or a WRN mutation + 3 cardinal signs. A diagnosis is suspected if an individual has 2 cardinal signs or 1 cardinal sign + additional signs  Cardinal signs*  Additional signs  Premature greying or thinning of scalp hair  Abnormal glucose and/or lipid metabolism  Bilateral cataracts  Skeletal abnormalities (osteoporosis)  Characteristic dermatologic changes (atrophic skin, tight skin, clavus, callus, intractable skin ulcers)  Malignant tumors (nonepithelial tumors, thyroid cancer)  Soft-tissue calcification (Achilles tendon)  Parental consanguinity  ‘Bird-like’ facies  Premature atherosclerosis (angina pectoris, myocardial infarction)  Abnormal voice (high pitched, squeaky, hoarse)  Hypogonadism    Short stature and low bodyweight  *Age of onset between 10-40 years. View Large The WRN gene is located on chromosome 8p12 and encodes for a protein with DNA helicase activity that is a member of the RecQ family.52,58 The WRN protein product uses its helicase function to help resolve intermediate DNA structures generated during DNA metabolism and also functions in DNA repair (specifically base excision repair and double-stranded DNA break repair) replication, transcription, and telomere maintenance.59 Its loss of function in Werner syndrome patients leads to genomic instability and limited replicative capacity in somatic cells.60,61 The majority of pathogenic germline mutations leading to Werner syndrome are stop codons, small indels, or splicing mutations that cause loss of the nuclear localization of the protein. Other mutations lead to protein instability and loss of function, but essentially all WRN mutations are functional null alleles in Werner syndrome.62 Sporadic meningiomas are characterized by a number of chromosomal copy number alterations, and this appears to increase with meningioma grade and tumor progression (Figure 3).63,64 The most common alteration is monosomy 22, followed by loss of chromosome 1p and 14q. Other chromosomal changes include loss of 6q, 10, and 18q as well as gain of chromosomes 1q, 9q, 12q, 15q, 17q, and 20q.65 In particular, combined 1p/14q deletions are significantly more likely in higher-grade meningiomas and 14q deletions are more likely in benign recurrent meningiomas.64 It has been postulated that mutations in WRN and other DNA helicases may result in such chromosomal changes, given their role in proper DNA replication and repair. WRN silencing through promoter methylation has been investigated.66 Li et al66 found that meningiomas had a significantly higher WRN methylation rate than did healthy arachnoid control tissue. Subsequently, WRN was expressed significantly less in meningioma tissue than in normal arachnoid tissue. WRN promoter hypermethylation has been investigated in other cancers, and was found to be most prevalent in colorectal, non-small cell lung, gastric, prostate, and thyroid cancers.67 In addition, loss of WRN function led to chromosomal instability in these cancers. Given that many sporadic meningiomas have DNA changes that could be related to dysfunction of WRN or WRN-like proteins, the role of DNA repair and replication enzymes in sporadic meningiomas may be a relevant topic for further investigation. FIGURE 3. View largeDownload slide Mutations involved in meningioma progression. Gain of function mutations shown in red, loss of function mutations in black. Familial mutations are shown on the top, sporadic mutations and chromosomal changes are shown on the bottom. FIGURE 3. View largeDownload slide Mutations involved in meningioma progression. Gain of function mutations shown in red, loss of function mutations in black. Familial mutations are shown on the top, sporadic mutations and chromosomal changes are shown on the bottom. BAP1 Tumor Predisposition Syndrome The oncogenicity of the BAP1 gene was originally discovered in the genomic assessment of families with uveal melanoma and malignant mesothelioma.68 Further studies on BAP1 indicated that several other neoplasms including meningioma are included in the syndrome (Table 6). A hallmark feature of these patients is the presence of melanocytic BAP1-mutated atypical intradermal tumors (MBAITs).69 MBAITs are skin-colored, dome-shaped papules that appear in up to two-thirds of carriers, typically before other associated malignancies develop. Given that this is a more recently discovered syndrome, prevalence and penetrance data are scarce, and the phenotypic spectrum of associated tumors continues to expand.68 TABLE 6. Tumors Associated With BAP1 Tumor Predisposition Syndrome   Uveal melanoma    Malignant mesothelioma    Renal cell carcinoma    Cutaneous melanoma    Meningioma    Melanocytic bap1-mutated atypical intradermal tumors    Uveal melanoma    Malignant mesothelioma    Renal cell carcinoma    Cutaneous melanoma    Meningioma    Melanocytic bap1-mutated atypical intradermal tumors  View Large TABLE 6. Tumors Associated With BAP1 Tumor Predisposition Syndrome   Uveal melanoma    Malignant mesothelioma    Renal cell carcinoma    Cutaneous melanoma    Meningioma    Melanocytic bap1-mutated atypical intradermal tumors    Uveal melanoma    Malignant mesothelioma    Renal cell carcinoma    Cutaneous melanoma    Meningioma    Melanocytic bap1-mutated atypical intradermal tumors  View Large BAP1 is located on chromosome 3p21.1 and encodes the BRCA1-associated protein 1, which functions in transcription, chromatin modification, and DNA damage response. Part of its tumor suppressive function is related to its interaction with BRCA1, which plays an important role in the repair of double-stranded DNA breaks and has been well described in breast cancer predisposition and development.68,70 Meningiomas were identified as part of the BAP1 tumor predisposition syndrome when examining a group of patients with uveal melanoma.71 In this study, a germline truncating mutation of BAP1 was identified in 5 individuals of the same family. One family member had a diagnosis of meningioma, and subsequent tumor tissue analysis revealed biallelic inactivation of BAP1. The BAP1 gene has also been found to be inactivated in a subset of high-grade rhabdoid meningiomas.72 Initially thought to be sporadic tumors, germline BAP1 mutations were identified in some of these patients, further supporting meningiomas as part of the BAP1 tumor predisposition syndrome spectrum. In this series, somatic BAP1 mutations were a predictor of clinically aggressive tumors, highlighting how genetic characterization of meningiomas can guide clinical management. It is also recommended that patients with somatic BAP1-mutated meningiomas be evaluated for BAP1 tumor predisposition syndrome, illustrating an instance where genetic testing in meningiomas should be completed. Germline genetic testing for BAP1 mutations is commercially available. A BAP1 antibody is available for immunohistochemistry (IHC) testing of patient samples, and in the study listed above all BAP1 mutants showed loss of BAP1 expression on IHC.72 SMARCE1 Germline mutations of SMARCE1 have been implicated in several families with familial meningiomatosis.73,74SMARCE1 is also known as BAF57, and is thought to be involved in loss of apoptosis in other types of cancer, including breast, ovarian, and prostate.75 Located on chromosome 17q21, SMARCE1 encodes for a subunit of the SWI/SNF complex, which regulates chromatin structure by nucleosome remodeling.76 Specifically, SMARCE1 is responsible for inducing apoptosis by stimulating expression of CYLD.77 SMARCE1 mutations have been investigated in the germline of families with a history of meningiomas as well as sporadic tumors.73 Smith et al73 examined SMARCE1 mutations in a group of patients with spinal meningiomas and a positive family history of meningiomas that tested negative for germline mutations in NF2. Whole exome sequencing with Sanger confirmation revealed heterozygous loss-of-function mutations in SMARCE1 in these patients. The histology on all of these tumors was of the clear-cell subtype, and the loss of function phenotype was thought to be consistent with a tumor suppressor mechanism. The authors concluded that the SWI/SNF complex plays a key role in the pathogenesis of meningiomas, and that they had identified a new discrete entity with a genetic basis for multiple meningiomas. This work has been further corroborated by the identification of a family with a germline SMARCE1 mutation and cranial meningiomas.74 Additionally, in 1 cohort of patients less than 25 years of age with a solitary meningioma, germline SMARCE1 mutations were identified in 14% (9/63) of patients.78 All affected individuals also had meningiomas of the clear cell type. These studies have important clinical management implications when a clear cell meningioma is encountered in clinical practice, especially in young patients or those with a family history of meningiomas. Germline genetic testing for SMARCE1 mutations should be considered in this subset of patients as part of their work-up. Individuals with an identified mutation should be followed more closely given their predilection for multiple lesions, and their family members should be offered predictive genetic testing for risk stratification. IHC investigating the SMARCE1 status of patient samples has been previously performed, and loss of SMARCE1 protein staining appears specific to clear cell histology.79,80 However, IHC and genomic profiling of tumor specimens do not routinely include evaluation of SMARCE1 at this time. SMARCB1 Similar to SMARCE1, SMARCB1 (also known as INI1) encodes a protein that serves as a subunit of the SWI/SNF complex.81 It is located on chromosome 22q11.23, in close proximity to the NF2 gene. Germline inactivating mutations of SMARCB1 have been found to predispose patients to several cancers including malignant rhabdoid tumors and schwannomatosis, both independently and as part of a 4-hit mechanism with NF2.82-84 In a study examining a family with schwannomatosis and a germline SMARCB1 mutation, multiple family members were also noted to have 1 or more meningiomas, independent of an NF2 mutation.85 In a similar fashion to schwannomatosis, SMARCB1 mutations have been described as part of a 4-hit mechanism in a family with multiple meningiomas with a germline SMARCB1 mutation and somatic NF2 mutations.86 In this particular group of patients, this complement of mutations appeared to preferentially produce meningiomas of the falx cerebri. This study also screened newly found carriers of the SMARCB1 mutation for intracranial lesions by magnetic resonance imaging of the brain and found that 7 of 11 these patients had asymptomatic lesions. All of these lesions appeared to be meningiomas, and all of them were attached to falx. In a patient with a falcine meningioma and a family history of meningioma, germline genetic testing for SMARCB1 mutations should be considered, which would also allow for the subsequent risk stratification of family members. IHC is also readily available to test tissue samples for loss of SMARCB1(INI1) expression. However, the identified mutations in the studies above were missense mutations and it is unclear if they will affect overall protein abundance, potentially limiting the value of IHC. The role of SMARCB1 has been investigated in sporadic tumors as well. In 1 series of sporadic meningiomas, somatic mutations in exon 9 of SMARCB1 were noted in 3% of tumors.87 An insertional mutation in exon 9 of SMARCB1 was also noted in 1 patient in an 80 patient series of sporadic meningiomas by a separate group.88 Other Familial Syndromes Other syndromes including MEN1 and Rubinstein-Taybi syndrome have been reported to be associated with meningiomas, but have only been demonstrated in case reports and case series.89,90 DISCUSSION A set of common themes emerges when looking at the work done on familial disease and the extension of that work to examine sporadic cases. With the notable exception of NF2, most of these genes are not commonly mutated in sporadic disease. However, they are all involved in pathways or processes that appear essential to meningioma formation. These pathways include or involve SHH, AKT-PI3K-mTOR, and YAP/TAZ. SHH pathway mutations lead to uncontrolled cell growth and proliferation in many cancers, while AKT-PI3K-mTOR pathway malfunction leads mainly to increased survival.23,40 YAP/TAZ signaling dysfunction through merlin mutations produces increased proliferation through the loss of contact inhibition.12 Merlin is also involved with regulation of the mTOR pathway, a potential point of convergence in these important pathways in meningioma pathogenesis.91 Another common theme between the familial syndromes presented is that the protein products of the mutated genes commonly function in DNA maintenance and repair (Figure 4). This is particularly interesting given the chromosomal copy number and other large-scale genetic changes that occur in meningioma. These changes are even more prevalent in higher-grade tumors, suggesting an essential role in the pathogenesis of meningioma progression. While it is known that these changes occur, the exact mechanism by which they occur and the ultimate effects of these changes remains to be elucidated. FIGURE 4. View largeDownload slide Meningioma-associated mutations in genes involving chromatin structure and the DNA damage response. WRN codes for a protein that is a member of the RecQ family. Its helicase function serves broad functional roles in normal DNA metabolism as well as DNA repair. The BAP1 protein is involved in the DNA damage response, specifically functioning in double-stranded break repair. The SMARCB1 and SMARCE1 genes code for components of the SWI/SNF complex, which participates in chromatin remodeling to regulate transcription. FIGURE 4. View largeDownload slide Meningioma-associated mutations in genes involving chromatin structure and the DNA damage response. WRN codes for a protein that is a member of the RecQ family. Its helicase function serves broad functional roles in normal DNA metabolism as well as DNA repair. The BAP1 protein is involved in the DNA damage response, specifically functioning in double-stranded break repair. The SMARCB1 and SMARCE1 genes code for components of the SWI/SNF complex, which participates in chromatin remodeling to regulate transcription. This work supports the strategy of examining familial syndromes to identify candidate genes and pathways for further study in sporadic cases. The relationship of SMARCE1 mutations to the clear cell subtype and BAP1 mutations to the rhabdoid subtype demonstrate how familial studies also provide insight into the specific histopathologic subtypes of meningioma. The histologic grading of meningiomas is challenging given the multitude of types, and the discordance between histology and clinical behavior lessens its utility. Studies in which specific genetic mutations are associated with specific histologies are the beginning of a potential molecular classification of these tumors that could be used to better predict patient outcomes. Epigenetic classification schemes are also a potential method for classification, with a recently proposed scheme based on DNA methylation for meningiomas being an example.92 The authors found that methylation patterns profiled meningiomas into 2 major groups with several subclasses and that this profiling better predicted recurrence and prognosis than the current WHO classification. The authors included the familial genes SMARCE1, SMARCB1, PTEN, SUFU, and NF2 in their analysis of the subtypes of their classification scheme, with NF2 and SUFU being the only genes that segregated significantly. Investigating the other familial genes discussed in this review could have provided the authors further information. We agree with the authors and WHO that given the complex nature of these tumors, an amalgamated approach combining histology, genetics, epigenetics, and clinical findings will provide the best system for classification. The results of studies on familial syndromes combined with large-scale genetic studies on sporadic meningioma leave up to 20% of meningiomas without a genetic basis. Given the comprehensive examination of the genetic landscape of meningioma that these studies provide, one hypothesis that could be derived is that the remaining causes of meningioma lay outside of genetic mutations. Studies examining gene expression profiles, epigenetic regulation, microRNA, and long noncoding RNA will be important to gain a better understanding of meningioma pathogenesis. CONCLUSION Here we present a comprehensive review of the familial syndromes associated with meningiomas. 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Exp Ther Med . 2015; 10( 2): 498- 502. Google Scholar CrossRef Search ADS PubMed  67. Agrelo R, Cheng WH, Setien F et al.   Epigenetic inactivation of the premature aging werner syndrome gene in human cancer. Proc Natl Acad Sci USA . 2006; 103( 23): 8822- 8827. Google Scholar CrossRef Search ADS PubMed  68. Murali R, Wiesner T, Scolyer RA. Tumours associated with BAP1 mutations. Pathology . 2013; 45( 2): 116- 126. Google Scholar CrossRef Search ADS PubMed  69. Haugh AM, Njauw CN, Bubley JA et al.   Genotypic and phenotypic features of BAP1 cancer syndrome. JAMA Dermatol  2017;( 10). doi: 10.1001/jamadermatol.2017.2330. 70. Johannsson OT, Idvall I, Anderson C et al.   Tumour biological features of BRCA1-induced breast and ovarian cancer. Eur J Cancer . 1997; 33( 3): 362- 371. Google Scholar CrossRef Search ADS PubMed  71. Abdel-Rahman MH, Pilarski R, Cebulla CM et al.   Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet . 2011; 48( 12): 856- 859. Google Scholar CrossRef Search ADS PubMed  72. Shankar GM, Abedalthagafi M, Vaubel RA et al.   Germline and somatic BAP1 mutations in high-grade rhabdoid meningiomas. Neuro Oncol . 2017; 19( 4): 535- 545. Google Scholar PubMed  73. Smith MJ, O'Sullivan J, Bhaskar SS et al.   Loss-of-function mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat Genet . 2013; 45( 3): 295- 298. Google Scholar CrossRef Search ADS PubMed  74. Gerkes EH, Fock JM, den Dunnen WF et al.   A heritable form of SMARCE1-related meningiomas with important implications for follow-up and family screening. Neurogenetics . 2016; 17( 2): 83- 89. Google Scholar CrossRef Search ADS PubMed  75. Garcia-Pedrero JM, Kiskinis E, Parker MG, Belandia B. The SWI/SNF chromatin remodeling subunit BAF57 is a critical regulator of estrogen receptor function in breast cancer cells. J Biol Chem . 2006; 281( 32): 22656- 22664. Google Scholar CrossRef Search ADS PubMed  76. Kazantseva A, Sepp M, Kazantseva J et al.   N-terminally truncated BAF57 isoforms contribute to the diversity of SWI/SNF complexes in neurons. J Neurochem . 2009; 109( 3): 807- 818. Google Scholar CrossRef Search ADS PubMed  77. Wang L, Baiocchi RA, Pal S, Mosialos G, Caligiuri M, Sif S. The BRG1- and hBRM-associated factor BAF57 induces apoptosis by stimulating expression of the cylindromatosis tumor suppressor gene. Mol Cell Biol . 2005; 25( 18): 7953- 7965. Google Scholar CrossRef Search ADS PubMed  78. Pathmanaban ON, Sadler KV, Kamaly-Asl ID et al.   Association of genetic predisposition with solitary schwannoma or meningioma in children and young adults. JAMA Neurol . 2017;( 9). doi: 10.1001/jamaneurol.2017.1406. 79. Smith MJ, Ahn S, Lee JI, Bulman M, Plessis DD, Suh YL. SMARCE1 mutation screening in classification of clear cell meningiomas. Histopathology . 2017; 70( 5): 814- 820. Google Scholar CrossRef Search ADS PubMed  80. Tauziede-Espariat A, Parfait B, Besnard A et al.   Loss of SMARCE1 expression is a specific diagnostic marker of clear cell meningioma: A comprehensive immunophenotypical and molecular analysis. Brain Pathol . 2017. doi: 10.1111/bpa.12524. 81. Smith MJ, Wallace AJ, Bowers NL et al.   Frequency of SMARCB1 mutations in familial and sporadic schwannomatosis. Neurogenetics . 2012; 13( 2): 141- 145. Google Scholar CrossRef Search ADS PubMed  82. Hadfield KD, Newman WG, Bowers NL et al.   Molecular characterisation of SMARCB1 and NF2 in familial and sporadic schwannomatosis. J Med Genet . 2008; 45( 6): 332- 339. Google Scholar CrossRef Search ADS PubMed  83. Hulsebos TJ, Plomp AS, Wolterman RA, Robanus-Maandag EC, Baas F, Wesseling P. Germline mutation of INI1/SMARCB1 in familial schwannomatosis. Am J Hum Genet . 2007; 80( 4): 805- 810. Google Scholar CrossRef Search ADS PubMed  84. Sevenet N, Sheridan E, Amram D, Schneider P, Handgretinger R, Delattre O. Constitutional mutations of the hSNF5/INI1 gene predispose to a variety of cancers. Am J Hum Genet . 1999; 65( 5): 1342- 1348. Google Scholar CrossRef Search ADS PubMed  85. Bacci C, Sestini R, Provenzano A et al.   Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation. Neurogenetics . 2010; 11( 1): 73- 80. Google Scholar CrossRef Search ADS PubMed  86. van den Munckhof P, Christiaans I, Kenter SB, Baas F, Hulsebos TJ. Germline SMARCB1 mutation predisposes to multiple meningiomas and schwannomas with preferential location of cranial meningiomas at the falx cerebri. Neurogenetics . 2012; 13( 1): 1- 7. Google Scholar CrossRef Search ADS PubMed  87. Schmitz U, Mueller W, Weber M, Sevenet N, Delattre O, von Deimling A. INI1 mutations in meningiomas at a potential hotspot in exon 9. Br J Cancer . 2001; 84( 2): 199- 201. Google Scholar CrossRef Search ADS PubMed  88. Rieske P, Zakrzewska M, Piaskowski S et al.   Molecular heterogeneity of meningioma with INI1 mutation. Mol Pathol . 2003; 56( 5): 299- 301. Google Scholar CrossRef Search ADS PubMed  89. Asgharian B, Chen YJ, Patronas NJ et al.   Meningiomas may be a component tumor of multiple endocrine neoplasia type 1. Clin Cancer Res . 2004; 10( 3): 869- 880. Google Scholar CrossRef Search ADS PubMed  90. Verstegen MJ, van den Munckhof P, Troost D, Bouma GJ. Multiple meningiomas in a patient with Rubinstein-Taybi syndrome. J Neurosurg . 2005; 102( 1): 167- 168. Google Scholar CrossRef Search ADS PubMed  91. James MF, Han S, Polizzano C et al.   NF2/merlin is a novel negative regulator of mTOR complex 1, and activation of mTORC1 is associated with meningioma and schwannoma growth. Mol Cell Biol . 2009; 29( 15): 4250- 4261. Google Scholar CrossRef Search ADS PubMed  92. Sahm F, Schrimpf D, Stichel D et al.   DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol . 2017; 18( 5): 682- 694. Google Scholar CrossRef Search ADS PubMed  ACKNOWLEDGMENTS Meenakshi B. Bhattarcharjee, MD for her pathology slides for Figure 3 and Leomar Y. Ballester, MD, PhD for his assistance in discussion of the clinical pathology elements of the manuscript. Supplemental digital content is available for this article at www.neurosurgery-online.com. Supplemental Digital Content. Appendix. List of Included Studies. This list provides the studies that were included after the literature review with the provided search terms. COMMENT This manuscript presents a summary of known genomic drivers of familial meningiomas and how they help in dissecting the pathogenesis of sporadic cases. Stephen Yip Vancouver, Canada © Congress of Neurological Surgeons 2018. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Neurosurgery Oxford University Press

Familial Syndromes Involving Meningiomas Provide Mechanistic Insight Into Sporadic Disease

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Oxford University Press
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© Congress of Neurological Surgeons 2018.
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0148-396X
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1524-4040
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Abstract

Abstract Currently, there is an incomplete understanding of the molecular pathogenesis of meningiomas, the most common primary brain tumor. Several familial syndromes are characterized by increased meningioma risk, and the genetics of these syndromes provides mechanistic insight into sporadic disease. The best defined of these syndromes is neurofibromatosis type 2, which is caused by a mutation in the NF2 gene and has a meningioma incidence of approximately 50%. This finding led to the subsequent discovery that NF2 loss-of-function occurs in up to 60% of sporadic tumors. Other important familial diseases with increased meningioma risk include nevoid basal cell carcinoma syndrome, multiple endocrine neoplasia 1 (MEN1), Cowden syndrome, Werner syndrome, BAP1 tumor predisposition syndrome, Rubinstein-Taybi syndrome, and familial meningiomatosis caused by germline mutations in the SMARCB1 and SMARCE1 genes. For each of these syndromes, the diagnostic criteria, incidence in the population, and frequency of meningioma are presented to review the relevant clinical information for these conditions. The genetic mutations, molecular pathway derangements, and relationship to sporadic disease for each syndrome are described in detail to identify targets for further investigation. Familial syndromes characterized by meningiomas often affect genes and pathways that are also implicated in a subset of sporadic cases, suggesting key molecular targets for therapeutic intervention. Further studies are needed to resolve the functional relevance of specific genes whose significance in sporadic disease remains to be elucidated. Familial meningioma, Meningioma, Meningioma genetics, Meningioma pathogenesis ABBREVIATIONS ABBREVIATIONS AKT1 v-Akt murine thymoma viral oncogene homolog 1 BCC basal cell carcinoma CS Cowden syndrome IHC immunohistochemistry KLF4 Kruppel-like factor 4 MBAIT melanocytic BAP1-mutated atypical intradermal tumors MEN1 multiple endocrine neoplasia 1 NBCCS nevoid basal cell carcinoma syndrome NF2 neurofibromatosis type 2 PHTS PTEN hamartoma tumor syndrome PI3K phosphatidylinositol 3-kinase PTEN phosphatase and tensin homolog SHH sonic hedgehog SMO smoothened TRAF7 TNF receptor-associated factor 7 Meningiomas are the most common primary brain tumor reported in the United States, comprising approximately 36% of brain tumors.1,2 Estimates from recent data predict that more than 20 000 new meningiomas will be diagnosed each year, with an incidence of 7.5 per 100 000.2 While the majority of these tumors are sporadic, there are many familial syndromes that place a patient at increased risk for meningioma development. The most well characterized and documented of these genetic syndromes is neurofibromatosis type 2 (NF2). Identification of the NF2 gene led to the investigation of molecular genetic mutations in sporadic meningiomas, in which up to 60% of patients have also been found to have somatic inactivation of NF2.3,4 Recent whole genome sequencing and whole exome sequencing studies in non-NF2 mutated meningiomas have further delineated additional mutations in TRAF7, KLF4, AKT1, PI3K, and SMO; however, many sporadic tumors still have not been found to have a genetic basis (Figure 1).5,6 Greater understanding of the familial syndromes associated with meningiomatosis may elucidate further molecular mechanisms behind the development of sporadic meningiomas. Below, we present a review of familial syndromes associated with meningioma predisposition. FIGURE 1. View largeDownload slide Locations of known mutations in meningioma. Loss of chromosome regions shown in black, gain of chromosome regions shown in red. FIGURE 1. View largeDownload slide Locations of known mutations in meningioma. Loss of chromosome regions shown in black, gain of chromosome regions shown in red. METHODS A review of the PubMed database was conducted to identify published studies on known familial meningioma syndromes up until June 2017. Combinations of search terms used included “meningioma,” “familial meningiomatosis,” “familial meningioma,” “nevoid basal cell carcinoma syndrome,” “Gorlin syndrome,” “multiple endocrine neoplasia 1,” “Cowden syndrome,” “Werner syndrome,” “BAP1 tumor predisposition syndrome,” “SMARCB1,” “SMARCE1,” “SUFU,” and “Rubinstein-Taybi syndrome.” Only studies available in English were included. All identified abstracts from these searches were analyzed, and those that reviewed or examined familial syndromes associated with meningiomas were included. RESULTS A review of PubMed abstracts from the described search criteria resulted in 46 studies that met inclusion (see Supplemental Digital Content). The results from these studies are presented below and include NF2, nevoid basal cell carcinoma syndrome (NBCCS, also known as Gorlin syndrome), multiple endocrine neoplasia 1 (MEN1), Cowden syndrome (CS), Werner syndrome, BAP1 tumor predisposition syndrome, Rubinstein-Taybi syndrome, and familial meningiomatosis caused by germline mutations in the SMARCB1 and SMARCE1 genes (Table 1). TABLE 1. List of Syndromes, Mutations, Pathways, and Sporadic Relationships Syndrome  Mutated gene  Involved pathway  Relationship to sporadic tumors  NF2  NF2 tumor suppressor  EGFR, YAP/TAZ, MAPK, cytoskeletal architecture  Mutated in 40%-60%  Werner  WRN  DNA processing, maintenance and repair  Methylated with decrease in expression  BAP1-TPDS  BAP1  Chromatin Remodeling, DNA repair  Found in high-grade rhabdoid meningiomas  SMARCE1  SMARCE1  Nucleosome remodeling, apoptosis  Found in Clear cell meningiomas  SMARCB1  SMARCB1  Nucleosome remodeling, apoptosis  Mutated in 3%  Gorlin  PTCH1  SHH – PTCH1/SMO/SUFU/GLI-1,2,3  SMO mutated in 5%  Cowden  PTEN  PI3K – RTK/AKT/PI3K/mTOR/PTEN  AKT mutated in 14%; PIK3CA mutated in 7%  Syndrome  Mutated gene  Involved pathway  Relationship to sporadic tumors  NF2  NF2 tumor suppressor  EGFR, YAP/TAZ, MAPK, cytoskeletal architecture  Mutated in 40%-60%  Werner  WRN  DNA processing, maintenance and repair  Methylated with decrease in expression  BAP1-TPDS  BAP1  Chromatin Remodeling, DNA repair  Found in high-grade rhabdoid meningiomas  SMARCE1  SMARCE1  Nucleosome remodeling, apoptosis  Found in Clear cell meningiomas  SMARCB1  SMARCB1  Nucleosome remodeling, apoptosis  Mutated in 3%  Gorlin  PTCH1  SHH – PTCH1/SMO/SUFU/GLI-1,2,3  SMO mutated in 5%  Cowden  PTEN  PI3K – RTK/AKT/PI3K/mTOR/PTEN  AKT mutated in 14%; PIK3CA mutated in 7%  View Large TABLE 1. List of Syndromes, Mutations, Pathways, and Sporadic Relationships Syndrome  Mutated gene  Involved pathway  Relationship to sporadic tumors  NF2  NF2 tumor suppressor  EGFR, YAP/TAZ, MAPK, cytoskeletal architecture  Mutated in 40%-60%  Werner  WRN  DNA processing, maintenance and repair  Methylated with decrease in expression  BAP1-TPDS  BAP1  Chromatin Remodeling, DNA repair  Found in high-grade rhabdoid meningiomas  SMARCE1  SMARCE1  Nucleosome remodeling, apoptosis  Found in Clear cell meningiomas  SMARCB1  SMARCB1  Nucleosome remodeling, apoptosis  Mutated in 3%  Gorlin  PTCH1  SHH – PTCH1/SMO/SUFU/GLI-1,2,3  SMO mutated in 5%  Cowden  PTEN  PI3K – RTK/AKT/PI3K/mTOR/PTEN  AKT mutated in 14%; PIK3CA mutated in 7%  Syndrome  Mutated gene  Involved pathway  Relationship to sporadic tumors  NF2  NF2 tumor suppressor  EGFR, YAP/TAZ, MAPK, cytoskeletal architecture  Mutated in 40%-60%  Werner  WRN  DNA processing, maintenance and repair  Methylated with decrease in expression  BAP1-TPDS  BAP1  Chromatin Remodeling, DNA repair  Found in high-grade rhabdoid meningiomas  SMARCE1  SMARCE1  Nucleosome remodeling, apoptosis  Found in Clear cell meningiomas  SMARCB1  SMARCB1  Nucleosome remodeling, apoptosis  Mutated in 3%  Gorlin  PTCH1  SHH – PTCH1/SMO/SUFU/GLI-1,2,3  SMO mutated in 5%  Cowden  PTEN  PI3K – RTK/AKT/PI3K/mTOR/PTEN  AKT mutated in 14%; PIK3CA mutated in 7%  View Large Neurofibromatosis Type 2 NF2 is an autosomal dominant, 100% penetrant condition characterized by a constellation of schwannomas and meningiomas.7 NF2 is clinically diagnosed using the Manchester criteria, the details of which are in Table 2. The overall prevalence of NF2 in the population is approximately 1 in 60 000.8 TABLE 2. Neurofibromatosis Type 2 Diagnostic Criteria   A diagnosis can be made if an individual meets one of the following:    Bilateral vestibular schwannomas    A first degree relative with NF2 + unilateral vestibular schwannoma or 2 NF2-associated lesions*    Unilateral vestibular schwannoma + 2 NF2-associated lesions*    Multiple meningiomas + unilateral vestibular schwannoma or 2 other NF-2 associated lesions*    A diagnosis can be made if an individual meets one of the following:    Bilateral vestibular schwannomas    A first degree relative with NF2 + unilateral vestibular schwannoma or 2 NF2-associated lesions*    Unilateral vestibular schwannoma + 2 NF2-associated lesions*    Multiple meningiomas + unilateral vestibular schwannoma or 2 other NF-2 associated lesions*  *Meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities. View Large TABLE 2. Neurofibromatosis Type 2 Diagnostic Criteria   A diagnosis can be made if an individual meets one of the following:    Bilateral vestibular schwannomas    A first degree relative with NF2 + unilateral vestibular schwannoma or 2 NF2-associated lesions*    Unilateral vestibular schwannoma + 2 NF2-associated lesions*    Multiple meningiomas + unilateral vestibular schwannoma or 2 other NF-2 associated lesions*    A diagnosis can be made if an individual meets one of the following:    Bilateral vestibular schwannomas    A first degree relative with NF2 + unilateral vestibular schwannoma or 2 NF2-associated lesions*    Unilateral vestibular schwannoma + 2 NF2-associated lesions*    Multiple meningiomas + unilateral vestibular schwannoma or 2 other NF-2 associated lesions*  *Meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities. View Large NF2 is caused by germline mutations in the NF2 tumor suppressor gene, located at 22q12.2. The protein product is called merlin or schwannomin.9 Within the cell, merlin has been found to interact with several proteins that affect PI3K, YAP/TAZ, and mitogen-activated protein kinase (MAPK) signaling. All 3 pathways are important in cell growth and cellular proliferation.8,10,11 Given its location at the cell membrane-cytoskeletal interface, several other potential functions have been proposed, including contact-dependent inhibition of EGFR, effects on cell-to-cell adhesion, and regulation of cytoskeletal architecture.12-14 The role of NF2 inactivation in sporadic meningiomas was investigated due to the high frequency of meningiomas in NF2 patients. The frequency of NF2 inactivation is estimated to be present between in 40% and 60% of cases of sporadic meningiomas based on several studies, and this mutation is thought to be the causative mutation in these cases.4 Interestingly, NF2-mutated meningiomas have certain location predilections.5 Those with NF2 mutations and/or chromosome 22 loss were found preferentially in the hemispheres. For meningiomas of the skull base, those located laterally and posteriorly were significantly more likely to have NF2 mutations and/or chromosome 22 loss, whereas medially located skull base tumors were more commonly non-NF2 mutated. The work on NF2 has provided an excellent example of how investigating a familial syndrome with meningiomas can lead to establishing the genetic basis for sporadic disease. Nevoid Basal Cell Carcinoma Syndrome Nevoid basal cell carcinoma syndrome, also known as basal cell nevus syndrome or Gorlin syndrome, is an autosomal dominant syndrome that is classically characterized by multiple basal cell carcinomas (BCC), jaw keratocysts, and bifid ribs.15 The complete list of major clinical criteria required for diagnosis and cited by several studies is detailed in Table 3. 16,20 The estimated prevalence is between 1 in 30 000 and 1 in 256 000 and equally affects men and women.16,17 Additional tumors that are associated with the syndrome include meningiomas and rhabdomyosarcomas.16,18 TABLE 3. Nevoid Basal Cell Carcinoma Syndrome Diagnostic Criteria   A diagnosis can be made if an individual meets 2 major criteria or 1 major + 2 minor criteria  Major criteria  Minor criteria  Basal cell carcinomas: ≥5 in a lifetime or 1 diagnosed before age 30  Childhood medulloblastoma  Lamellar calcification of the falx before the age of 20  Lympho-mesenteric or pleural cysts  Jaw odontogenic keratocyst  Macrocephaly (occipitofrontal circumference (OFC) > 97th percentile)  Palmar or plantar pits: ≥2  Cleft lip/palate  First-degree relative with NBCCS  Vertebral or rib anomalies (bifid/splayed/extra ribs, bifid vertebrae)    Preaxial or postaxial polydactyly    Ovarian or cardiac fibromas    Ocular anomalies (cataract, developmental defects, pigmentary changes of the retinal epithelium)    A diagnosis can be made if an individual meets 2 major criteria or 1 major + 2 minor criteria  Major criteria  Minor criteria  Basal cell carcinomas: ≥5 in a lifetime or 1 diagnosed before age 30  Childhood medulloblastoma  Lamellar calcification of the falx before the age of 20  Lympho-mesenteric or pleural cysts  Jaw odontogenic keratocyst  Macrocephaly (occipitofrontal circumference (OFC) > 97th percentile)  Palmar or plantar pits: ≥2  Cleft lip/palate  First-degree relative with NBCCS  Vertebral or rib anomalies (bifid/splayed/extra ribs, bifid vertebrae)    Preaxial or postaxial polydactyly    Ovarian or cardiac fibromas    Ocular anomalies (cataract, developmental defects, pigmentary changes of the retinal epithelium)  View Large TABLE 3. Nevoid Basal Cell Carcinoma Syndrome Diagnostic Criteria   A diagnosis can be made if an individual meets 2 major criteria or 1 major + 2 minor criteria  Major criteria  Minor criteria  Basal cell carcinomas: ≥5 in a lifetime or 1 diagnosed before age 30  Childhood medulloblastoma  Lamellar calcification of the falx before the age of 20  Lympho-mesenteric or pleural cysts  Jaw odontogenic keratocyst  Macrocephaly (occipitofrontal circumference (OFC) > 97th percentile)  Palmar or plantar pits: ≥2  Cleft lip/palate  First-degree relative with NBCCS  Vertebral or rib anomalies (bifid/splayed/extra ribs, bifid vertebrae)    Preaxial or postaxial polydactyly    Ovarian or cardiac fibromas    Ocular anomalies (cataract, developmental defects, pigmentary changes of the retinal epithelium)    A diagnosis can be made if an individual meets 2 major criteria or 1 major + 2 minor criteria  Major criteria  Minor criteria  Basal cell carcinomas: ≥5 in a lifetime or 1 diagnosed before age 30  Childhood medulloblastoma  Lamellar calcification of the falx before the age of 20  Lympho-mesenteric or pleural cysts  Jaw odontogenic keratocyst  Macrocephaly (occipitofrontal circumference (OFC) > 97th percentile)  Palmar or plantar pits: ≥2  Cleft lip/palate  First-degree relative with NBCCS  Vertebral or rib anomalies (bifid/splayed/extra ribs, bifid vertebrae)    Preaxial or postaxial polydactyly    Ovarian or cardiac fibromas    Ocular anomalies (cataract, developmental defects, pigmentary changes of the retinal epithelium)  View Large Specifically, meningiomas were reported in 5% of NBCCS patients in 2 studies.19,20 Given that meningiomas commonly arise from the falx cerebri, it is interesting to note that NBCCS is characterized by prominent calcifications of this area.16,19 The genetic causes behind NBCCS are pathogenic mutations in genes of the sonic hedgehog (SHH) signaling pathway including PTCH1, PTCH2, and SUFU, located at 9q22.32, 1p34.1, and 10q24.32, respectively, with variations in PTCH1 being the most common.21,22 The activation of this pathway drives cell proliferation in both normal neural development and in tumor development.23 In BCC and a subset of medulloblastoma, the loss of PTCH1 or SUFU and the activation of SMO have been implicated in tumor initiation and maintenance.24,25 In fact, mutations in PTCH1 or SMO are sufficient to drive tumorigenesis in BCC and medulloblastoma mouse models.23,26,27 The PTCH1 gene codes for a protein that constitutes the ligand-binding component of the SHH receptor complex. The details of the SHH pathway are depicted in Figure 2.28,29 FIGURE 2. View largeDownload slide Details of the SHH and Akt pathways. Without SHH binding, PTCH1 renders smoothened (SMO) inactive and inhibits it from signaling downstream targets. When SHH binds to PTCH1, SMO is released from this inhibition, allowing it to interact with SUFU. This results in the activation and nuclear translocation of glioma-associated oncogene homologue 1 (GLI1) and (GLI2), and the degradation of GLI3. In the Akt pathway, PTEN normally targets IP3 to inhibit the phosphorylation of Akt. When growth factor (GF) binding to receptor tyrosine kinases (RTK) occurs, PI3K signaling is increased, leading to IP3 accumulation, phosphorylation of Akt and activation of downstream targets. FIGURE 2. View largeDownload slide Details of the SHH and Akt pathways. Without SHH binding, PTCH1 renders smoothened (SMO) inactive and inhibits it from signaling downstream targets. When SHH binds to PTCH1, SMO is released from this inhibition, allowing it to interact with SUFU. This results in the activation and nuclear translocation of glioma-associated oncogene homologue 1 (GLI1) and (GLI2), and the degradation of GLI3. In the Akt pathway, PTEN normally targets IP3 to inhibit the phosphorylation of Akt. When growth factor (GF) binding to receptor tyrosine kinases (RTK) occurs, PI3K signaling is increased, leading to IP3 accumulation, phosphorylation of Akt and activation of downstream targets. A meningioma has been reported in a patient with NBCCS with a confirmed germline PTCH1 mutation in which the genetic sequencing of the patient's meningioma revealed an additional somatic mutation in PTCH1. Using the Knudson's 2-hit theory, they considered the development of this meningioma to be caused by loss of function of PTCH1.30 Additionally, driver mutations in SMO have been identified as one of the most common non-NF2 mutations in sporadic meningiomas, and have a predilection for the olfactory groove. Meningiomas with an SMO mutation in the olfactory groove have been found to have a higher recurrence rate, especially late recurrences (>5 yr). Given this information and the significance with regard to prognostication, surgeons and neuro-oncologists should consider testing olfactory groove meningiomas specifically for SMO mutations and adjusting their follow-up schedule accordingly for these lesions, which is currently commercially available at multiple CLIA (Clinical Laboratory Improvement Amendments)-certified laboratories.5,31 Patients with NBCCS caused by SUFU mutations have been found to be significantly more likely to have a meningioma in comparison to NBCCS patients caused by PTCH1 or PTCH2 mutations.22SUFU mutations have also been investigated in a family with multiple meningiomas and the absence of other features of NBCCS.32 Genome-wide linkage analysis and exome sequencing in this family found that germline SUFU mutations segregated with disease in the family. Functional studies showed that the identified mutation led to significantly increased SHH pathway activation due to loss of the normal suppressor function of SUFU. This group also sequenced the coding exons and exon-intron boundaries of SUFU in blood/germline samples of 162 meningiomas (11 of these patients had a familial history of meningiomas and 40 had multiple meningiomas) from a national meningioma database; however, no pathogenic variants of SUFU were detected. The SHH pathway is critical to the formation of meningiomas in some instances. Studies on patients with NBCCS and familial meningiomatosis due to germline SUFU mutations have provided important information into the mechanisms by which derangement of the SHH pathway can lead to these tumors. Further research into the other components of this pathway is important. Cowden Syndrome Cowden syndrome, part of the PTEN hamartoma tumor syndrome (PHTS), is an autosomal dominant disorder caused by germline mutations in phosphatase and tensin homolog (PTEN) on chromosome 10q23.31.33 Its diagnostic criteria include a host of major and minor criteria as well as pathognomonic findings listed in Table 4.34 CS is estimated to affect between 1 in 200 000 and 1 in 250 000 people.35,36 Although not part of the major or minor criteria, meningiomas are found in approximately 8% of patients.37 Other clinical syndromes that are classified as PHTS include Bannayan-Riley-Ruvalcaba and Proteus syndrome.33 Multiple case reports have also identified meningiomas in patients with Proteus syndrome.38,39 TABLE 4. Cowden Syndrome Diagnostic Criteria   A diagnosis can be made if an individual meets 3 major criteria (1 must be macrocephaly, LDD, or GI hamartomas) or 2 major + 3 minor criteria*  Major criteria  Minor criteria  Breast cancer  Autism spectrum disorder  Endometrial cancer (epithelial)  Colon cancer  Thyroid cancer (follicular)  Esophageal glycogenic acanthosis: ≥ 3  Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps): ≥ 3  Lipomas: ≥ 3  Adult Lhermitte-Duclos disease (LDD)  Intellectual disability (IQ ≤ 75)  Macrocephaly (occipitofrontal circumference (OFC) ≥ 97th percentile)  Renal cell carcinoma  Macular pigmentation of the glans penis  Testicular lipomatosis  Multiple mucocutaneous lesions (any of the following):  Thyroid cancer (papillary or follicular variant of papillary)  Trichilemmomas: ≥ 3, at least one biopsy proven  Thyroid lesions (adenoma, multinodular goiter)  Acral keratoses: ≥ 3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)  Vascular anomalies (including multiple intracranial developmental venous anomalies)  Mucocutaneous neuromas: ≥ 3    Oral papillomas (particularly on tongue and gingiva): ≥ 3 or 1 biopsy proven/dermatologist diagnosed      A diagnosis can be made if an individual meets 3 major criteria (1 must be macrocephaly, LDD, or GI hamartomas) or 2 major + 3 minor criteria*  Major criteria  Minor criteria  Breast cancer  Autism spectrum disorder  Endometrial cancer (epithelial)  Colon cancer  Thyroid cancer (follicular)  Esophageal glycogenic acanthosis: ≥ 3  Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps): ≥ 3  Lipomas: ≥ 3  Adult Lhermitte-Duclos disease (LDD)  Intellectual disability (IQ ≤ 75)  Macrocephaly (occipitofrontal circumference (OFC) ≥ 97th percentile)  Renal cell carcinoma  Macular pigmentation of the glans penis  Testicular lipomatosis  Multiple mucocutaneous lesions (any of the following):  Thyroid cancer (papillary or follicular variant of papillary)  Trichilemmomas: ≥ 3, at least one biopsy proven  Thyroid lesions (adenoma, multinodular goiter)  Acral keratoses: ≥ 3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)  Vascular anomalies (including multiple intracranial developmental venous anomalies)  Mucocutaneous neuromas: ≥ 3    Oral papillomas (particularly on tongue and gingiva): ≥ 3 or 1 biopsy proven/dermatologist diagnosed    *In an individual who has a relative who meets the above criteria or has a PTEN mutation, a diagnosis can be made if he or she meets 2 major criteria, 1 major + 2 minor criteria, or 3 minor criteria. View Large TABLE 4. Cowden Syndrome Diagnostic Criteria   A diagnosis can be made if an individual meets 3 major criteria (1 must be macrocephaly, LDD, or GI hamartomas) or 2 major + 3 minor criteria*  Major criteria  Minor criteria  Breast cancer  Autism spectrum disorder  Endometrial cancer (epithelial)  Colon cancer  Thyroid cancer (follicular)  Esophageal glycogenic acanthosis: ≥ 3  Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps): ≥ 3  Lipomas: ≥ 3  Adult Lhermitte-Duclos disease (LDD)  Intellectual disability (IQ ≤ 75)  Macrocephaly (occipitofrontal circumference (OFC) ≥ 97th percentile)  Renal cell carcinoma  Macular pigmentation of the glans penis  Testicular lipomatosis  Multiple mucocutaneous lesions (any of the following):  Thyroid cancer (papillary or follicular variant of papillary)  Trichilemmomas: ≥ 3, at least one biopsy proven  Thyroid lesions (adenoma, multinodular goiter)  Acral keratoses: ≥ 3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)  Vascular anomalies (including multiple intracranial developmental venous anomalies)  Mucocutaneous neuromas: ≥ 3    Oral papillomas (particularly on tongue and gingiva): ≥ 3 or 1 biopsy proven/dermatologist diagnosed      A diagnosis can be made if an individual meets 3 major criteria (1 must be macrocephaly, LDD, or GI hamartomas) or 2 major + 3 minor criteria*  Major criteria  Minor criteria  Breast cancer  Autism spectrum disorder  Endometrial cancer (epithelial)  Colon cancer  Thyroid cancer (follicular)  Esophageal glycogenic acanthosis: ≥ 3  Gastrointestinal hamartomas (including ganglioneuromas, but excluding hyperplastic polyps): ≥ 3  Lipomas: ≥ 3  Adult Lhermitte-Duclos disease (LDD)  Intellectual disability (IQ ≤ 75)  Macrocephaly (occipitofrontal circumference (OFC) ≥ 97th percentile)  Renal cell carcinoma  Macular pigmentation of the glans penis  Testicular lipomatosis  Multiple mucocutaneous lesions (any of the following):  Thyroid cancer (papillary or follicular variant of papillary)  Trichilemmomas: ≥ 3, at least one biopsy proven  Thyroid lesions (adenoma, multinodular goiter)  Acral keratoses: ≥ 3 palmoplantar keratotic pits and/or acral hyperkeratotic papules)  Vascular anomalies (including multiple intracranial developmental venous anomalies)  Mucocutaneous neuromas: ≥ 3    Oral papillomas (particularly on tongue and gingiva): ≥ 3 or 1 biopsy proven/dermatologist diagnosed    *In an individual who has a relative who meets the above criteria or has a PTEN mutation, a diagnosis can be made if he or she meets 2 major criteria, 1 major + 2 minor criteria, or 3 minor criteria. View Large The PTEN protein acts as a phosphatase to dephosphorylate various cellular lipids and proteins. Dysfunctional PTEN leads to upregulation of the PI3K-AKT-mTOR (mammalian target of rapamycin) pathway, resulting in increases in cell proliferation, energy metabolism, and survival.40 It has been found to be important in breast and prostate cancer as well as glioblastoma multiforme.41 In mouse models of glioma, PTEN deletion results in earlier tumor onset and increases tumor grade.42,43 PTEN targets include phosphatidylinositol trisphosphate and phosphatidylinositol bisphosphate, both products of PI3K. This pathway is illustrated in Figure 2. As part of its protein phosphatase activity, PTEN has been shown to dephosphorylate focal adhesion kinase, which has negative effects on cell migration and cell spreading, as well as MAPK that regulates cell survival.44,45 In sporadic meningiomas, higher-grade tumors are associated with progressive changes at the chromosomal level including losses of chromosomes 1p, 9q, 10q, 14q, and 22q.46 Given this information and PTEN’s location at 10q23.3, it was investigated as a candidate gene in sporadic meningiomas.47 Using a group of 55 WHO grade I, 10 grade II, and 10 grade III meningiomas, Peters et al47 sequenced the entire coding sequence of the PTEN gene in tumor samples. No PTEN mutations were seen in the grade I tumors, but 1 grade III tumor harbored a somatic mutation in PTEN. These findings led them to hypothesize that mutations in PTEN are unlikely to be involved in the initiation and formation of low-grade meningiomas, but may contribute to malignant progression to higher-grade lesions. Such a conclusion supports other work in the chromosomal analysis comparing high-grade and low-grade sporadic meningiomas.46 This is similar to gliomas in that low-grade gliomas do not have as high of a frequency of PTEN loss as high-grade gliomas.48 Given PTEN’s role in regulation of the PI3K-AKT-mTOR pathway, and evidence of dysregulation of this pathway in many cancers, downstream targets of PTEN have also been investigated as potential oncogenic drivers in meningioma.49 Both AKT and PI3KA mutations have been found in sporadic meningiomas, comprising approximately 9% and 7% of non-NF2-mutant meningiomas, respectively.5,50 The complexity of this pathway suggests ample room for more investigation into the role of both PTEN and its downstream targets in meningioma pathogenesis. Previous research in patients with CS has provided some of the framework for our understanding of this pathway's role in cancer. Werner Syndrome Werner syndrome, also known as adult progeria, was first described in a set of siblings with short stature, “senile” appearance, premature graying of the hair, early-onset cataracts, dermatologic changes, and muscle atrophy.51 Biallelic mutations in the WRN gene (also known as RECQL2) were later established as the cause of the syndrome, which is inherited in an autosomal recessive manner.52 A set of cardinal and additional signs and symptoms has been designated and was updated most recently in 2013 (Table 5).53 A definite diagnosis is achieved when all 6 cardinal signs are present or a gene mutation and at least 3 cardinal signs are present. Interestingly, Japan has the highest frequency of carriers, at rates of 6 per 1000, while the disease prevalence in the overall population is estimated to be 1 in 1000 000 individuals based on publically available allele frequency databases.54,55 A patient with Werner syndrome is approximately 36.2 times Standardized Incidence Ratio (SIR); 95% confidence interval 17.3, 66.5) more likely to develop a meningioma than the general population and are more likely to develop them at a younger age.56 In addition, the proportion of meningiomas to other brain tumors in the Werner Syndrome is higher than expected.57 TABLE 5. Werner Syndrome Diagnostic Criteria   A confirmed diagnosis can be made if an individual has all 6 cardinal signs or a WRN mutation + 3 cardinal signs. A diagnosis is suspected if an individual has 2 cardinal signs or 1 cardinal sign + additional signs  Cardinal signs*  Additional signs  Premature greying or thinning of scalp hair  Abnormal glucose and/or lipid metabolism  Bilateral cataracts  Skeletal abnormalities (osteoporosis)  Characteristic dermatologic changes (atrophic skin, tight skin, clavus, callus, intractable skin ulcers)  Malignant tumors (nonepithelial tumors, thyroid cancer)  Soft-tissue calcification (Achilles tendon)  Parental consanguinity  ‘Bird-like’ facies  Premature atherosclerosis (angina pectoris, myocardial infarction)  Abnormal voice (high pitched, squeaky, hoarse)  Hypogonadism    Short stature and low bodyweight    A confirmed diagnosis can be made if an individual has all 6 cardinal signs or a WRN mutation + 3 cardinal signs. A diagnosis is suspected if an individual has 2 cardinal signs or 1 cardinal sign + additional signs  Cardinal signs*  Additional signs  Premature greying or thinning of scalp hair  Abnormal glucose and/or lipid metabolism  Bilateral cataracts  Skeletal abnormalities (osteoporosis)  Characteristic dermatologic changes (atrophic skin, tight skin, clavus, callus, intractable skin ulcers)  Malignant tumors (nonepithelial tumors, thyroid cancer)  Soft-tissue calcification (Achilles tendon)  Parental consanguinity  ‘Bird-like’ facies  Premature atherosclerosis (angina pectoris, myocardial infarction)  Abnormal voice (high pitched, squeaky, hoarse)  Hypogonadism    Short stature and low bodyweight  *Age of onset between 10-40 years. View Large TABLE 5. Werner Syndrome Diagnostic Criteria   A confirmed diagnosis can be made if an individual has all 6 cardinal signs or a WRN mutation + 3 cardinal signs. A diagnosis is suspected if an individual has 2 cardinal signs or 1 cardinal sign + additional signs  Cardinal signs*  Additional signs  Premature greying or thinning of scalp hair  Abnormal glucose and/or lipid metabolism  Bilateral cataracts  Skeletal abnormalities (osteoporosis)  Characteristic dermatologic changes (atrophic skin, tight skin, clavus, callus, intractable skin ulcers)  Malignant tumors (nonepithelial tumors, thyroid cancer)  Soft-tissue calcification (Achilles tendon)  Parental consanguinity  ‘Bird-like’ facies  Premature atherosclerosis (angina pectoris, myocardial infarction)  Abnormal voice (high pitched, squeaky, hoarse)  Hypogonadism    Short stature and low bodyweight    A confirmed diagnosis can be made if an individual has all 6 cardinal signs or a WRN mutation + 3 cardinal signs. A diagnosis is suspected if an individual has 2 cardinal signs or 1 cardinal sign + additional signs  Cardinal signs*  Additional signs  Premature greying or thinning of scalp hair  Abnormal glucose and/or lipid metabolism  Bilateral cataracts  Skeletal abnormalities (osteoporosis)  Characteristic dermatologic changes (atrophic skin, tight skin, clavus, callus, intractable skin ulcers)  Malignant tumors (nonepithelial tumors, thyroid cancer)  Soft-tissue calcification (Achilles tendon)  Parental consanguinity  ‘Bird-like’ facies  Premature atherosclerosis (angina pectoris, myocardial infarction)  Abnormal voice (high pitched, squeaky, hoarse)  Hypogonadism    Short stature and low bodyweight  *Age of onset between 10-40 years. View Large The WRN gene is located on chromosome 8p12 and encodes for a protein with DNA helicase activity that is a member of the RecQ family.52,58 The WRN protein product uses its helicase function to help resolve intermediate DNA structures generated during DNA metabolism and also functions in DNA repair (specifically base excision repair and double-stranded DNA break repair) replication, transcription, and telomere maintenance.59 Its loss of function in Werner syndrome patients leads to genomic instability and limited replicative capacity in somatic cells.60,61 The majority of pathogenic germline mutations leading to Werner syndrome are stop codons, small indels, or splicing mutations that cause loss of the nuclear localization of the protein. Other mutations lead to protein instability and loss of function, but essentially all WRN mutations are functional null alleles in Werner syndrome.62 Sporadic meningiomas are characterized by a number of chromosomal copy number alterations, and this appears to increase with meningioma grade and tumor progression (Figure 3).63,64 The most common alteration is monosomy 22, followed by loss of chromosome 1p and 14q. Other chromosomal changes include loss of 6q, 10, and 18q as well as gain of chromosomes 1q, 9q, 12q, 15q, 17q, and 20q.65 In particular, combined 1p/14q deletions are significantly more likely in higher-grade meningiomas and 14q deletions are more likely in benign recurrent meningiomas.64 It has been postulated that mutations in WRN and other DNA helicases may result in such chromosomal changes, given their role in proper DNA replication and repair. WRN silencing through promoter methylation has been investigated.66 Li et al66 found that meningiomas had a significantly higher WRN methylation rate than did healthy arachnoid control tissue. Subsequently, WRN was expressed significantly less in meningioma tissue than in normal arachnoid tissue. WRN promoter hypermethylation has been investigated in other cancers, and was found to be most prevalent in colorectal, non-small cell lung, gastric, prostate, and thyroid cancers.67 In addition, loss of WRN function led to chromosomal instability in these cancers. Given that many sporadic meningiomas have DNA changes that could be related to dysfunction of WRN or WRN-like proteins, the role of DNA repair and replication enzymes in sporadic meningiomas may be a relevant topic for further investigation. FIGURE 3. View largeDownload slide Mutations involved in meningioma progression. Gain of function mutations shown in red, loss of function mutations in black. Familial mutations are shown on the top, sporadic mutations and chromosomal changes are shown on the bottom. FIGURE 3. View largeDownload slide Mutations involved in meningioma progression. Gain of function mutations shown in red, loss of function mutations in black. Familial mutations are shown on the top, sporadic mutations and chromosomal changes are shown on the bottom. BAP1 Tumor Predisposition Syndrome The oncogenicity of the BAP1 gene was originally discovered in the genomic assessment of families with uveal melanoma and malignant mesothelioma.68 Further studies on BAP1 indicated that several other neoplasms including meningioma are included in the syndrome (Table 6). A hallmark feature of these patients is the presence of melanocytic BAP1-mutated atypical intradermal tumors (MBAITs).69 MBAITs are skin-colored, dome-shaped papules that appear in up to two-thirds of carriers, typically before other associated malignancies develop. Given that this is a more recently discovered syndrome, prevalence and penetrance data are scarce, and the phenotypic spectrum of associated tumors continues to expand.68 TABLE 6. Tumors Associated With BAP1 Tumor Predisposition Syndrome   Uveal melanoma    Malignant mesothelioma    Renal cell carcinoma    Cutaneous melanoma    Meningioma    Melanocytic bap1-mutated atypical intradermal tumors    Uveal melanoma    Malignant mesothelioma    Renal cell carcinoma    Cutaneous melanoma    Meningioma    Melanocytic bap1-mutated atypical intradermal tumors  View Large TABLE 6. Tumors Associated With BAP1 Tumor Predisposition Syndrome   Uveal melanoma    Malignant mesothelioma    Renal cell carcinoma    Cutaneous melanoma    Meningioma    Melanocytic bap1-mutated atypical intradermal tumors    Uveal melanoma    Malignant mesothelioma    Renal cell carcinoma    Cutaneous melanoma    Meningioma    Melanocytic bap1-mutated atypical intradermal tumors  View Large BAP1 is located on chromosome 3p21.1 and encodes the BRCA1-associated protein 1, which functions in transcription, chromatin modification, and DNA damage response. Part of its tumor suppressive function is related to its interaction with BRCA1, which plays an important role in the repair of double-stranded DNA breaks and has been well described in breast cancer predisposition and development.68,70 Meningiomas were identified as part of the BAP1 tumor predisposition syndrome when examining a group of patients with uveal melanoma.71 In this study, a germline truncating mutation of BAP1 was identified in 5 individuals of the same family. One family member had a diagnosis of meningioma, and subsequent tumor tissue analysis revealed biallelic inactivation of BAP1. The BAP1 gene has also been found to be inactivated in a subset of high-grade rhabdoid meningiomas.72 Initially thought to be sporadic tumors, germline BAP1 mutations were identified in some of these patients, further supporting meningiomas as part of the BAP1 tumor predisposition syndrome spectrum. In this series, somatic BAP1 mutations were a predictor of clinically aggressive tumors, highlighting how genetic characterization of meningiomas can guide clinical management. It is also recommended that patients with somatic BAP1-mutated meningiomas be evaluated for BAP1 tumor predisposition syndrome, illustrating an instance where genetic testing in meningiomas should be completed. Germline genetic testing for BAP1 mutations is commercially available. A BAP1 antibody is available for immunohistochemistry (IHC) testing of patient samples, and in the study listed above all BAP1 mutants showed loss of BAP1 expression on IHC.72 SMARCE1 Germline mutations of SMARCE1 have been implicated in several families with familial meningiomatosis.73,74SMARCE1 is also known as BAF57, and is thought to be involved in loss of apoptosis in other types of cancer, including breast, ovarian, and prostate.75 Located on chromosome 17q21, SMARCE1 encodes for a subunit of the SWI/SNF complex, which regulates chromatin structure by nucleosome remodeling.76 Specifically, SMARCE1 is responsible for inducing apoptosis by stimulating expression of CYLD.77 SMARCE1 mutations have been investigated in the germline of families with a history of meningiomas as well as sporadic tumors.73 Smith et al73 examined SMARCE1 mutations in a group of patients with spinal meningiomas and a positive family history of meningiomas that tested negative for germline mutations in NF2. Whole exome sequencing with Sanger confirmation revealed heterozygous loss-of-function mutations in SMARCE1 in these patients. The histology on all of these tumors was of the clear-cell subtype, and the loss of function phenotype was thought to be consistent with a tumor suppressor mechanism. The authors concluded that the SWI/SNF complex plays a key role in the pathogenesis of meningiomas, and that they had identified a new discrete entity with a genetic basis for multiple meningiomas. This work has been further corroborated by the identification of a family with a germline SMARCE1 mutation and cranial meningiomas.74 Additionally, in 1 cohort of patients less than 25 years of age with a solitary meningioma, germline SMARCE1 mutations were identified in 14% (9/63) of patients.78 All affected individuals also had meningiomas of the clear cell type. These studies have important clinical management implications when a clear cell meningioma is encountered in clinical practice, especially in young patients or those with a family history of meningiomas. Germline genetic testing for SMARCE1 mutations should be considered in this subset of patients as part of their work-up. Individuals with an identified mutation should be followed more closely given their predilection for multiple lesions, and their family members should be offered predictive genetic testing for risk stratification. IHC investigating the SMARCE1 status of patient samples has been previously performed, and loss of SMARCE1 protein staining appears specific to clear cell histology.79,80 However, IHC and genomic profiling of tumor specimens do not routinely include evaluation of SMARCE1 at this time. SMARCB1 Similar to SMARCE1, SMARCB1 (also known as INI1) encodes a protein that serves as a subunit of the SWI/SNF complex.81 It is located on chromosome 22q11.23, in close proximity to the NF2 gene. Germline inactivating mutations of SMARCB1 have been found to predispose patients to several cancers including malignant rhabdoid tumors and schwannomatosis, both independently and as part of a 4-hit mechanism with NF2.82-84 In a study examining a family with schwannomatosis and a germline SMARCB1 mutation, multiple family members were also noted to have 1 or more meningiomas, independent of an NF2 mutation.85 In a similar fashion to schwannomatosis, SMARCB1 mutations have been described as part of a 4-hit mechanism in a family with multiple meningiomas with a germline SMARCB1 mutation and somatic NF2 mutations.86 In this particular group of patients, this complement of mutations appeared to preferentially produce meningiomas of the falx cerebri. This study also screened newly found carriers of the SMARCB1 mutation for intracranial lesions by magnetic resonance imaging of the brain and found that 7 of 11 these patients had asymptomatic lesions. All of these lesions appeared to be meningiomas, and all of them were attached to falx. In a patient with a falcine meningioma and a family history of meningioma, germline genetic testing for SMARCB1 mutations should be considered, which would also allow for the subsequent risk stratification of family members. IHC is also readily available to test tissue samples for loss of SMARCB1(INI1) expression. However, the identified mutations in the studies above were missense mutations and it is unclear if they will affect overall protein abundance, potentially limiting the value of IHC. The role of SMARCB1 has been investigated in sporadic tumors as well. In 1 series of sporadic meningiomas, somatic mutations in exon 9 of SMARCB1 were noted in 3% of tumors.87 An insertional mutation in exon 9 of SMARCB1 was also noted in 1 patient in an 80 patient series of sporadic meningiomas by a separate group.88 Other Familial Syndromes Other syndromes including MEN1 and Rubinstein-Taybi syndrome have been reported to be associated with meningiomas, but have only been demonstrated in case reports and case series.89,90 DISCUSSION A set of common themes emerges when looking at the work done on familial disease and the extension of that work to examine sporadic cases. With the notable exception of NF2, most of these genes are not commonly mutated in sporadic disease. However, they are all involved in pathways or processes that appear essential to meningioma formation. These pathways include or involve SHH, AKT-PI3K-mTOR, and YAP/TAZ. SHH pathway mutations lead to uncontrolled cell growth and proliferation in many cancers, while AKT-PI3K-mTOR pathway malfunction leads mainly to increased survival.23,40 YAP/TAZ signaling dysfunction through merlin mutations produces increased proliferation through the loss of contact inhibition.12 Merlin is also involved with regulation of the mTOR pathway, a potential point of convergence in these important pathways in meningioma pathogenesis.91 Another common theme between the familial syndromes presented is that the protein products of the mutated genes commonly function in DNA maintenance and repair (Figure 4). This is particularly interesting given the chromosomal copy number and other large-scale genetic changes that occur in meningioma. These changes are even more prevalent in higher-grade tumors, suggesting an essential role in the pathogenesis of meningioma progression. While it is known that these changes occur, the exact mechanism by which they occur and the ultimate effects of these changes remains to be elucidated. FIGURE 4. View largeDownload slide Meningioma-associated mutations in genes involving chromatin structure and the DNA damage response. WRN codes for a protein that is a member of the RecQ family. Its helicase function serves broad functional roles in normal DNA metabolism as well as DNA repair. The BAP1 protein is involved in the DNA damage response, specifically functioning in double-stranded break repair. The SMARCB1 and SMARCE1 genes code for components of the SWI/SNF complex, which participates in chromatin remodeling to regulate transcription. FIGURE 4. View largeDownload slide Meningioma-associated mutations in genes involving chromatin structure and the DNA damage response. WRN codes for a protein that is a member of the RecQ family. Its helicase function serves broad functional roles in normal DNA metabolism as well as DNA repair. The BAP1 protein is involved in the DNA damage response, specifically functioning in double-stranded break repair. The SMARCB1 and SMARCE1 genes code for components of the SWI/SNF complex, which participates in chromatin remodeling to regulate transcription. This work supports the strategy of examining familial syndromes to identify candidate genes and pathways for further study in sporadic cases. The relationship of SMARCE1 mutations to the clear cell subtype and BAP1 mutations to the rhabdoid subtype demonstrate how familial studies also provide insight into the specific histopathologic subtypes of meningioma. The histologic grading of meningiomas is challenging given the multitude of types, and the discordance between histology and clinical behavior lessens its utility. Studies in which specific genetic mutations are associated with specific histologies are the beginning of a potential molecular classification of these tumors that could be used to better predict patient outcomes. Epigenetic classification schemes are also a potential method for classification, with a recently proposed scheme based on DNA methylation for meningiomas being an example.92 The authors found that methylation patterns profiled meningiomas into 2 major groups with several subclasses and that this profiling better predicted recurrence and prognosis than the current WHO classification. The authors included the familial genes SMARCE1, SMARCB1, PTEN, SUFU, and NF2 in their analysis of the subtypes of their classification scheme, with NF2 and SUFU being the only genes that segregated significantly. Investigating the other familial genes discussed in this review could have provided the authors further information. We agree with the authors and WHO that given the complex nature of these tumors, an amalgamated approach combining histology, genetics, epigenetics, and clinical findings will provide the best system for classification. The results of studies on familial syndromes combined with large-scale genetic studies on sporadic meningioma leave up to 20% of meningiomas without a genetic basis. Given the comprehensive examination of the genetic landscape of meningioma that these studies provide, one hypothesis that could be derived is that the remaining causes of meningioma lay outside of genetic mutations. Studies examining gene expression profiles, epigenetic regulation, microRNA, and long noncoding RNA will be important to gain a better understanding of meningioma pathogenesis. CONCLUSION Here we present a comprehensive review of the familial syndromes associated with meningiomas. Details of the implicated genes and their associated pathways are given to facilitate further understanding of the molecular pathogenesis of meningiomas and to support future research. As many of the studies on these familial syndromes have shown, the molecular understanding of these syndromes often leads to investigations that broaden our understanding of sporadic disease. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article. REFERENCES 1. McNeill KA. Epidemiology of brain tumors. Neurol Clin . 2016; 34( 4): 981- 998. Google Scholar CrossRef Search ADS PubMed  2. Ostrom QT, Gittleman H, Liao P et al.   CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007-2011. Neuro Oncol . 2014; 16( suppl 4): iv1- iv63. Google Scholar CrossRef Search ADS PubMed  3. 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Sahm F, Schrimpf D, Stichel D et al.   DNA methylation-based classification and grading system for meningioma: a multicentre, retrospective analysis. Lancet Oncol . 2017; 18( 5): 682- 694. Google Scholar CrossRef Search ADS PubMed  ACKNOWLEDGMENTS Meenakshi B. Bhattarcharjee, MD for her pathology slides for Figure 3 and Leomar Y. Ballester, MD, PhD for his assistance in discussion of the clinical pathology elements of the manuscript. Supplemental digital content is available for this article at www.neurosurgery-online.com. Supplemental Digital Content. Appendix. List of Included Studies. This list provides the studies that were included after the literature review with the provided search terms. COMMENT This manuscript presents a summary of known genomic drivers of familial meningiomas and how they help in dissecting the pathogenesis of sporadic cases. Stephen Yip Vancouver, Canada © Congress of Neurological Surgeons 2018. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com

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NeurosurgeryOxford University Press

Published: Apr 11, 2018

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