Brain Tumor Pathol DOI 10.1007/s10014-016-0271-7 REVIEW ARTICLE Genetic landscape of meningioma Sayaka Yuzawa1,2 • Hiroshi Nishihara3,4 • Shinya Tanaka2,3 Received: 5 September 2016 / Accepted: 6 September 2016 Ó The Japan Society of Brain Tumor Pathology 2016 Abstract Meningioma is the most common intracranial tumor, arising from arachnoid cells of the meninges. Monosomy 22 and inactivating mutations of NF2 are wellknown genetic alterations of meningiomas. More recently, mutations in TRAF7, AKT1, KLF4, SMO, and PIK3CA were identified by next-generation sequencing. We here reviewed 553 meningiomas for the mutational patterns of the six genes. NF2 aberration was observed in 55 % of meningiomas. Mutations of TRAF7, AKT1, KLF4, PIK3CA, and SMO were identified in 20, 9, 9, 4.5, and 3 % of cases, respectively. Altogether, 80 % of cases harbored at least one of the genetic alterations in these genes. NF2 alterations and mutations of the other genes were mutually exclusive with a few exceptions. Clinicopathologically, tumors with mutations in TRAF7/AKT1 and SMO shared specific features: they were located in the anterior fossa, median middle fossa, or anterior calvarium, and most of them were meningothelial or transitional meningiomas. TRAF7/KLF4 type meningiomas showed different characteristics in that they occurred in the lateral middle fossa and median posterior fossa as well as anterior fossa and median middle & Sayaka Yuzawa [email protected] 1 Department of Diagnostic Pathology, Asahikawa Medical University, 2-1-1-1 Midorigaoka Higashi, Asahikawa, Hokkaido 078-8510, Japan 2 Department of Cancer Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 3 Department of Translational Pathology, Hokkaido University Graduate School of Medicine, Sapporo, Japan 4 Translational Research Laboratory, Hokkaido University Hospital, Clinical Research and Medical Innovation Center, Sapporo, Japan fossa, and contained a secretory meningioma component. We also discuss the mutational hotspots of these genes and other genetic/cytogenetic alterations contributing to tumorigenesis or progression of meningiomas. Keywords Meningioma Genetics Next-generation sequencers Introduction Meningioma is the most common brain tumor, accounting for 36.4 % of all primary brain tumors in the United States [1]. Meningiomas occur in all ages, with the exception of rare child cases [2], and the incidence rate increases with age [1]. Women are more likely to be affected, with a female:male ratio of 2.3:1 in non-malignant meningiomas [3]. Meningiomas are thought to arise from meningothelial cells covering the brain and spinal cord and exhibit various histological subtypes, including meningothelial, fibrous, psammomatous, microcystic, and secretory meningiomas. About 20 % of meningiomas are high-grade (WHO grade II–III) and show more aggressive behavior [4]. The recurrence rate of benign meningioma at 5 years after complete resection is approximately 10 % [5], whereas those of WHO grade II and III meningioma are about 50 and 80 %, respectively [6]. Loss of chromosome 22 was identified as the recurrent genetic alteration of meningiomas by fluorescence staining in the 1970s [7–9], and monosomy 22 was also reported in meningiomas of patients with neurofibromatosis type 2 [10], which is an autosomal dominant inherited disease characterized by bilateral acoustic schwannomas and multiple meningiomas. Furthermore, inactivating mutations of a tumor suppressor gene on chromosome 22q12 123 Brain Tumor Pathol were identified in sporadic and neurofibromatosis type 2 related meningiomas [11, 12], the genes encoding neurofibromin 2 (NF2; also known as merlin), a member of the protein 4.1 family of cytoskeletal associated proteins [13, 14]. Subsequently, NF2 gene aberration was identified in 40–60 % of sporadic meningiomas [15, 16]. Although some other genes on and out of chromosome 22 have also been suggested as candidate genes of meningioma, no critical genetic alterations were revealed until 2013. The development of next-generation sequencing changed the concept of the genetic status of meningiomas. Mutations of TNF receptor-associated factor 7 (TRAF7), vakt murine thymoma viral oncogene homolog 1 (AKT1), Krupplelike factor 4 (KLF4), and Smoothened, frizzled family receptor (SMO) were identified in non-NF2 meningioma [17]. Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha (PIK3CA) mutations were also detected in some meningiomas [17, 18]. In the recently updated WHO classification of the central nervous system (2016), gliomas and embryonal tumors are diagnosed according to both genetic and histological factors, such as ‘‘oligodendroglioma, IDH-mutant and 1p/ 19q-codeleted’’ [19]. However, the molecular diagnosis is not reflected in meningioma because the best-known prognostic marker is still histological phenotype. To clarify the accurate process of tumorigenesis and progression of each genotype, the accumulation of genetic status of meningioma is required. Here, we reviewed three articles with 553 meningiomas whose genetic status was clarified by next-generation sequencers, and investigated the frequency of each genetic alteration. In addition, we analyzed the mutational types, hotspots, and the correlation between genotypes and clinicopathological features in 637 cases described in seven articles. Other genetic alterations considered to contribute to the pathogenesis or progression of meningioma are also discussed. Frequency and pattern of the major genetic alterations (Fig. 1a) As of June 2016, three articles were published in which gene alterations of NF2, TRAF7, AKT1, KLF4, and SMO were examined by next-generation sequencing in [10 cases of meningioma [17, 18, 20]. Genetic information was extracted from 553 cases in the three studies. PIK3CA mutation was also assessed in 200 cases. Two articles [21, 22] were excluded from this analysis because they did not examine all the five genes. The frequency of each genetic alteration is described in Fig. 1a. Note that the mutation rate of PIK3CA in the Fig. 1a (pink) may be underestimated because PIK3CA 123 Fig. 1 a Frequency of each genetic alterations in meningiomas. The c ratio was calculated from the pooled data from 3 independent studies including 553 cases [17, 18, 20]. Note that the frequency of PIK3CA mutation (illustrated by pink in the figure) may be underestimated because PIK3CA was not included in the targeted sequencing panel in 2 articles [17, 20]. ‘‘Others’’ included cases with mutations in TRAF7, AKT1, KLF4, SMO and/or PIK3CA, but not categorized to TRAF7/ KLF4, TRAF7/AKT1, or SMO type. ‘‘Complex’’ are cases meeting both of the following two points; (1) at least one mutations in TRAF7, AKT1, KLF4, SMO and/or PIK3CA, and (2) NF2 loss and/or NF2 mutation. b Mutation hotspots of each gene. Mutations of NF2 were widely distributed in the whole genome, and almost all mutations are predicted to cause truncation of the protein. Ninety percent of mutations in TRAF7 were on the WD40 domains. All of the mutations of KLF4 and AKT1 were K409Q and E17K, respectively. The hotspot mutation of PIK3CA was H1047R and that of SMO were L412F and W535L was not included in the targeted sequencing in two articles [17, 20]. Eighty percent (442/553 cases) harbored at least one genetic alteration of the six genes including PIK3CA. NF2 aberration was identified in 55 % of meningiomas. About two-thirds of these cases harbored both NF2 loss and NF2 mutation. Ninety-seven percent of cases (197/203) with mutation in NF2 carried concomitant NF2 loss. TRAF7 mutation was observed in 20 % of meningiomas. More than 40 % of them (46/111 cases) also showed KLF4 mutation, whereas approximately a third of TRAF7 mutated meningiomas harbored concomitant AKT1 mutations. NF2 loss coexisted in four TRAF7 mutated meningiomas, two of which also showed AKT1 mutation and another one harbored mutation of PIK3CA. The overall mutation rates of AKT1 and KLF4 were both 9 %, and the mutations of these two genes were mutually exclusive. PIK3CA mutation was observed in 4.5 % of cases, although the number of cases examined is smaller than that of the other genes (200 vs. 553 cases). There were two other studies focusing on PIK3CA mutation in meningioma and the frequency of the gene mutation varied between the reports, although the mutation analysis was limited to hotspots in those two reports (exons 1/9/20, and exons 9/20, respectively) [23, 24]. Pang et al. [23] reported that one case out of 78 meningiomas (1 %) carried PIK3CA mutation. Bujko et al. [24] identified two PIK3CA mutations from 55 meningiomas (3.6 %), one of which was a silent mutation. Thus, more investigation is needed about the frequency of PIK3CA mutation. In the two articles analyzed here [17, 18], five of nine PIK3CA mutated cases harbored TRAF7 mutation, one of which also carried NF2 loss as described above. KLF4 mutation was identified in one case with PIK3CA mutation. PIK3CA and AKT1 mutation was mutually exclusive. Three percent of meningiomas showed mutations of SMO. Four of 18 cases (22 %) also showed NF2 loss and/ or NF2 mutation, and one case carried SMO and TRAF7 Brain Tumor Pathol Complex (2%) SMO (3%) A TRAF7/ KLF4 (8%) NF2 (53%) TRAF7/ AKT1 (6%) Others (8%) None (20%) Frequency NF2 loss 296/553 (54%) NF2 mut 203/553 (37%) TRAF7 111/553 (20%) KLF4 52/553 (9%) AKT1 49/553 (9%) PIK3CA 9/200 (4.5%) SMO 18/553 (3%) B NF2 595 aa 0 TRAF7 0 KLF4 RING Zf-TRAF W D-1 W D-2 W D-3 W D-4 W D-5 W D-6 W D-7 670 aa 504 aa 0 AKT1 480 aa 0 PIK3CA SMO 1068 aa 0 787 aa 0 Missense mutation Frameshift mutation Nonsense mutation Splice-site mutation Inframe In/del Silent mutation 123 Brain Tumor Pathol mutation. None of the SMO mutated meningiomas carried mutation in KLF4, AKT1, or PIK3CA. The types and distribution of mutations (Fig. 1b) We next investigated the distribution of mutations in NF2, TRAF7, AKT1, KLF4, PIK3CA, and SMO, by adding four articles with 84 cases [21–24]. Overall, 510 mutations (NF2, 231; TRAF7, 125; AKT1, 57; KLF4, 64; PIK3CA, 12; SMO, 21) were identified from 637 meningiomas. The distribution and types of mutations are described in Fig. 1b. KLF4 All of the KLF4 mutations were c.1225A[C (p.K409Q) (64/64 cases). KLF4 is a family of DNA-binding transcriptional regulators involving proliferation, differentiation, migration, inflammation and pluripotency [37, 38]. KLF4 is also reported as potential tumor suppressor gene in some cancers such as colorectal cancer, pancreatic ductal cancer, and lung cancer [39–41]. However, KLF4 K409Q is specific for meningioma and few cases with KLF4 K409Q in other tumors were identified. The mutated residue, K409, is located within the first zinc finger domain and makes direct DNA contact [17]. NF2 PIK3CA Mutations of NF2 were widely distributed in the whole gene, although 50 of the genes were more frequently affected. Almost all mutations are predicted to cause truncation of the protein, due to frameshift (44 %), nonsense (29 %), or splice-site mutations (24 %). TRAF7 Most of the mutations of TRAF7 (113/125 cases, 90 %) were on the WD40 domains. The most frequent mutation was N520S (25/125 cases, 20 %), followed by G536S (8 %), K615E (7 %), R641C (4 %), and R641H (4 %). TRAF7 is a proapoptotic N-terminal RING and zinc finger domain protein with E3 ubiquitin ligase activity. TRAF7 potentiates MEKK3-mediated signaling and regulates activation of NF-jB signaling [25]. RNA interference-mediated depletion of TRAF7 was thought to result in resistance to TNFa cytotoxicity [26]. In breast cancer, downregulation of TRAF7 expression was identified and p53 accumulation due to the defects of TRAF7-mediated ubiquitination was suggested [27]. However, the mutation of TRAF7 is highly specific for meningioma. The most frequent mutation pattern of PIK3CA in meningioma was H1047R (5/12, 42 %). R108H, E110del, N345K, HC419del, E453K, E545K, and T1025T were also reported in one case each. Among these mutations, PIK3CA H1047R and E545K were also reported as the hotspot mutants in other neoplasms, such as breast carcinoma, ovarian carcinoma, endometrial carcinoma, colorectal carcinoma, head and neck squamous cell carcinoma, and intraductal papillary mucinous neoplasm (IPMN) of the pancreas [42–47], and show constitutive phosphorylation of Akt [48, 49], promoting oncogenesis in various tumors. SMO The common mutation patterns of SMO were L412F (13/21, 62 %) and W535L (5/21, 24 %). SMO W535L was known as a hotspot mutation of basal cell carcinoma of the skin [50, 51], whereas L412F mutation was uncommon in other tumors with a few cases reported in medulloblastomas [52, 53]. Three rare SMO mutations, R113Q, L522V, and P647S, were identified, although all three of these cases carried concomitant NF2 loss, suggesting that the mutant SMO may not contribute to tumorigenesis in these cases. AKT1 Mutations of AKT1 were all c.49G[A (p.E17K) (57/57 cases). AKT1 E17K is also identified in various cancers such as breast, colorectal, lung, bladder, ovarian, and endometrial carcinoma [28–33]. AKT1 E17K causes constitutive AKT1 activation and promotes proliferation and tumor growth [28, 34]. Furthermore, mosaic AKT1 E17K mutation was identified in the majority of Proteus syndrome, a complex disorder characterized by the overgrowth of skin, connective tissue, brain, and other tissues [35]. Some cases with Proteus syndrome develop meningiomas [36]. 123 Clinicopathological features according to genotypes (Table 1; Fig. 2) We investigated the association with gene alterations and clinicopathological findings by the same cohort as Fig. 1b (637 cases). Meningiomas were classified into seven genotypes: NF2, TRAF7/KLF4, TRAF7/AKT1, SMO, ‘‘Others,’’ ‘‘Complex,’’ and ‘‘None.’’ NF2 type includes cases with NF2 loss and/or NF2 mutation but no other mutation in TRAF7, AKT1, KLF4, or PIK3CA. TRAF7/ KLF4 includes meningiomas with both TRAF7 and KLF4 Brain Tumor Pathol Table 1 Clinicopathological features according to genotype NF2 (n = 339) TRAF7/KLF4 (n = 56) TRAF7/AKT1 (n = 34) SMO (n = 17) Others (n = 57) Complex (n = 10) 57 (35–88) 52 (35–79) 55.5 (28–73) 53 (18–79) 56 (45–86) None (n = 124) Age Median (range) 58 (15–89) 54 (23–90) Sex Female (%) 232 (68 %) 48 (86 %) 24 (71 %) 13 (76 %) 43 (75 %) 9 (90 %) 91 (73 %) Male (%) 107 (32 %) 8 (14 %) 10 (29 %) 4 (24 %) 14 (25 %) 1 (10 %) 33 (27 %) 213 (63 %) 2 (1 %) 3 (5 %) 7 (13 %) 9 (26 %) 14 (41 %) 4 (24 %) 9 (53 %) 13 (23 %) 15 (26 %) 5 (50 %) 1 (10 %) 52 (42 %) 13 (10 %) Location Calvarium Anterior fossa Median middle fossa 15 (4 %) 11 (20 %) 8 (24 %) 4 (24 %) 11 (19 %) 0 (0 %) 22 (18 %) Lateral middle fossa 30 (9 %) 10 (18 %) 0 (0 %) 0 (0 %) 4 (7 %) 0 (0 %) 12 (10 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 3 (2 %) Anterior, median posterior fossa 7 (2 %) 11 (20 %) 2 (6 %) 0 (0 %) 3 (5 %) 1 (10 %) 7 (6 %) Posterior, lateral posterior fossa 36 (11 %) 1 (2 %) 0 (0 %) 0 (0 %) 4 (7 %) 0 (0 %) 8 (6 %) Posterior fossa, unknown 6 (2 %) 1 (2 %) 0 (0 %) 0 (0 %) 1 (2 %) 0 (0 %) 1 (1 %) Spinal 8 (2 %) 0 (0 %) 1 (3 %) 0 (0 %) 2 (4 %) 0 (0 %) 0 (0 %) Intraventricular 8 (2 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 1 (1 %) Orbital 3 (1 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) Middle fossa, unknown Multiple 10 (3 %) 2 (4 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 4 (3 %) Unknown 1 (0 %) 10 (18 %) 0 (0 %) 0 (0 %) 4 (7 %) 3 (30 %) 1 (1 %) Meningothelial 29 (9 %) 24 (43 %) 17 (50 %) 11 (65 %) 21 (37 %) 2 (20 %) 42 (34 %) Transitional Fibrous 62 (18 %) 70 (21 %) 6 (11 %) 0 (0 %) 7 (21 %) 0 (0 %) 3 (18 %) 0 (0 %) 12 (21 %) 3 (5 %) 1 (10 %) 0 (0 %) 22 (18 %) 7 (6 %) Psammomatous component 20 (6 %) 1 (2 %) 1 (3 %) 0 (0 %) 4 (7 %) 0 (0 %) 0 (0 %) Angiomatous component 13 (4 %) 1 (2 %) 0 (0 %) 0 (0 %) 1 (2 %) 0 (0 %) 15 (12 %) Microcystic component Histological subtypea 10 (3 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 6 (5 %) Secretory component 0 (0 %) 35 (63 %) 0 (0 %) 0 (0 %) 4 (7 %) 3 (30 %) 0 (0 %) Metaplastic 0 (0 %) 1 (2 %) 0 (0 %) 0 (0 %) 1 (2 %) 0 (0 %) 1 (1 %) Oncocytic 2 (1 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) Lymphoplasmacyte rich 1 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) Grade I, unknown 37 (11 %) 6 (11 %) 6 (18 %) 3 (18 %) 8 (14 %) 2 (20 %) 20 (16 %) Atypical 99 (29 %) 0 (0 %) 2 (6 %) 0 (0 %) 2 (4 %) 0 (0 %) 16 (13 %) Chordoid 3 (1 %) 0 (0 %) 0 (0 %) 0 (0 %) 2 (4 %) 2 (20 %) 1 (1 %) Clear cell 1 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) Anaplastic 10 (3 %) 0 (0 %) 0 (0 %) 0 (0 %) 2 (4 %) 0 (0 %) 4 (3 %) 0 (0 %) 0 (0 %) 1 (3 %) 0 (0 %) 0 (0 %) 0 (0 %) 0 (0 %) I II 224 (66 %) 105 (31 %) 56 (100 %) 0 (0 %) 31 (91 %) 2 (6 %) 17 (100 %) 0 (0 %) 51 (89 %) 4 (7 %) 8 (80 %) 2 (20 %) 103 (83 %) 17 (14 %) III 10 (3 %) 0 (0 %) 1 (3 %) 0 (0 %) 2 (4 %) 0 (0 %) 4 (3 %) Rhabdoid/papillary WHO grade Recurrence Yes 77 (23 %) 3 (5 %) 3 (9 %) 1 (6 %) 4 (7 %) 0 (0 %) 13 (10 %) No 77 (23 %) 13 (23 %) 8 (24 %) 7 (41 %) 15 (26 %) 2 (20 %) 35 (28 %) 185 (55 %) 40 (71 %) 23 (68 %) 9 (53 %) 38 (67 %) 8 (80 %) 76 (61 %) Unknown The data were collected from seven independent studies, including 637 meningioma cases [17, 18, 20–24]. The criteria of each genotype are described in the text a Some cases showed more than two histological subtypes 123 Brain Tumor Pathol A1 A2 B1 B2 C1 C2 D1 D2 Fig. 2 Magnetic resonance imaging with gadolinium administration and pathological findings of representative cases. a NF2 type (NF2 loss and NF2 p.E342*). The tumor was located in the right temporal convexity and showed fibrous meningioma with angiomatous and microcystic pattern. b TRAF7/AKT1 type (TRAF7 p.G536S and AKT1 p.E17K). Meningothelial meningiomas were observed in the anterior clinoid process. c TRAF7/KLF4 type (TRAF7 p.R641H and KLF4 p.K409Q). Petroclival meningioma showed meningothelial meningioma with secretory component. d SMO type (SMO p.W535L). The tumor was meningothelial meningioma of the paraclinoid mutations but no other genetic alterations. In the same way, TRF7/AKT1 contains cases with mutations in only TRAF7 and AKT1. Meningiomas harboring SMO L412F and W535L were categorized as SMO type, even if the cases carried concomitant NF2 loss. Three cases with NF2 loss and uncommon SMO mutation (R113Q, L522V, P647S) were classified as NF2 type. ‘‘Others’’ included cases with mutations in TRAF7, AKT1, KLF4, and/or PIK3CA, but not categorized as TRAF7/KLF4 or TRAF7/AKT1. One case with SMO L412F and TRAF7 T391N was also classified as ‘‘Others.’’ ‘‘Complex’’ is comprised of cases meeting both of the following two points: (1) at least one mutation in TRAF7, AKT1, KLF4, and/or PIK3CA, and (2) NF2 loss and/or NF2 mutation. ‘‘None’’ includes meningiomas without any mutations of the six genes or NF2 loss. The clinicopathological features of each genotype are described in Table 1. The classification of skull base meningiomas was followed by the previous reports (Clark et al.) [17] (Supplementary Table 1). The sum of the number of each histological type exceeds the total number of patients because an overlapping of histological subtypes is common in meningiomas. The magnetic resonance imaging (MRI) and hematoxylin and eosin (H&E) staining of the representative cases of each genotype are shown in Fig. 2. patients than the other genotypes, while TRAF7/KLF4 type exhibited female dominance. Genotypes were associated with the tumor location. More than 60 % of NF2 type was located in the calvarium including convexity of the skull, parasagittal region, and falx cerebri. The second and third common lesion of NF2 type was posterior, lateral posterior fossa (11 %) and lateral middle fossa (9 %), respectively. Approximately twothirds of TRAF7/AKT1 type was in anterior fossa or median middle fossa, and another 20 % was located in anterior convexity. Half of the meningiomas of SMO type were located in anterior fossa, and the remaining half were equally located in calvarium and median middle fossa, which shared a similar pattern to TRAF7/AKT1 type. As with TRAF7/AKT1 and SMO type, tumors of TRAF7/ KLF4 type were also distributed in anterior fossa (13 %) and median middle fossa (20 %), although lateral middle fossa (18 %) and anterior, median posterior fossa such as petroclival meningioma (20 %) were more common and calvarium was rare in TRAF7/KLF4 meningiomas. Clinical features Genotypes did not correlate with the patients’ age. Median age was 50s in all genotypes. NF2 type included more male 123 Pathological findings Histological subtypes were closely correlated with genotypes. Fibrous meningioma accounts for 21 % of NF2 type, and is uncommon in the other genotypes (0–6 %). Meningothelial and transitional meningiomas were frequently seen in TRAF7/AKT1 type (71 %) and SMO type (83 %). These two histological subtypes were also common in TRAF7/KLF4 type, although the most Brain Tumor Pathol NF2 (Fibrous/Transitional) TRAF7 KLF4 AKT1 PIK3CA SMO (Meningothelial/Transitional) (Secretory) Others Familial PTCH1 SUFU Grade I SMARCB1 Hyperdiploidy (ex. Chr 5 trisomy) (Angiomatous) Grade II TERT (Atypical) (Atypical) SMARCE1 (Clear cell) Grade III Loss of 1p, 6q, 10, 14q, 18q Gain of 1q, 9q, 12q, 15q, 17q, 20q CDKN2A/2B (Loss of 9p21) (Anaplastic) (Anaplastic) BRAF V600E (Rhabdoid) Fig. 3 The scheme of genetic/cytogenetic alterations in meningioma characteristic histological type of TRAF7/KLF4 type was the secretory component. The microcystic component was not observed in TRAF7/KLF4, TRAF7/AKT1, SMO, ‘‘Others,’’ or ‘‘Complex’’ types, and angiomatous component was also rare in these genotypes. All cases of TRAF7/KLF4 and SMO types were benign (WHO grade I), and most cases of TRAF7/AKT1 and ‘‘Others’’ type were also WHO grade I. On the other hand, 34 % of NF2 type meningiomas were WHO grade II–III. ‘‘Complex’’ type contained a slightly higher rate of highgrade meningioma, suggesting that ‘‘Complex’’ meningiomas are histologically intermediate between NF2 type and benign genotype. The rate of WHO grade II–III meningiomas was also slightly high in ‘‘None’’ type. Prognosis Information about prognosis could not be obtained in more than half of the cases; therefore, we could not accurately assess the relationship between genotype and prognosis. However, NF2 type tended to recur more frequently than the other genotypes. In addition, we have proposed ‘‘TRAKLS’’ type including meningiomas with mutation in TRAF7, AKT1, KLF4, and/or SMO as a good prognosis genotype. Recurrence rate of TRAKLS type was lower than NF2 type after adjustment for Simpson Grade, Ki-67 labeling index, and WHO grade [20]. Multivariate analyses including an adequate number of cases are needed. Other genes associated with tumorigenesis, malignancy or progression (Fig. 3) Various candidate genes were reported to be associated with tumorigenesis of meningiomas. Germline mutations of two subunits of the SWI/SNF chromatin remodeling complex, SMARCB1 [54–56] and SMARCE1 [57–61], were identified in familial meningiomas. Germline mutation or large gene deletion of SMARCE1, or chromosome loss including SMARCE1, causes pediatric and familial clear cell meningiomas [57–60]. On the other hand, SMARCB1, also known as INI1 and BAF47, is located on chromosome 22q11.23, and Christiaans et al. suggested the four-hit theory of tumor suppressor gene, involving SMARCB1 and NF2, in a subset of familial multiple meningiomas [55]. In addition, Schmitz et al. [62] identified the somatic SMARCB1 mutation in 4 of 126 sporadic meningiomas and Clark et al. [17] also detected somatic mutation of SMARCB1 in one out of 50 meningiomas. Germline mutation and second hit mutation or loss of heterozygosity (LOH) of the human homologue of the Drosophila patched gene, PTCH1 and suppressor of fused (SUFU) were also reported in meningioma [63, 64]. PTCH1 protein is thought to hold SMO in an inactive state and thus inhibit signaling to downstream genes [65]. PTCH1 inactivating mutation leads to activation of sonic hedgehog signaling. SUFU protein is the major negative regulator of the sonic hedgehog signaling, located 123 Brain Tumor Pathol downstream of SMO. The inactivating mutation of SUFU leads to dysregulated hedgehog signaling [63]. Therefore, these two gene alterations are thought to share the same oncogenic pathway as SMO type meningioma. Kijima et al. reported that both of two cases with germline mutations of PTCH1 or SUFU showed meningothelial meningiomas, one of which was suprasellar meningioma [64]. However, as Aavikko et al. [63] reported that no mutation of SUFU was found in additional 162 meningiomas, the SUFU mutation is extremely rare in sporadic meningioma. Other germline mutations associated with meningiomas include PTEN (Cowden syndrome), TP53 (Li–Fraumeni syndrome), VHL (von Hippel–Lindau disease), WRN (Werner syndrome), APC (Gardner syndrome), MEN1 (multiple endocrine neoplasia Type 1), and BAP1 [66–73], although the incidence rate of meningiomas in these hereditary diseases are varied. BRAF V600E mutation is one of the characteristic genetic alterations of gangliogliomas, pleomorphic xanthoastrocytomas, and epithelioid/rhabdoid glioblastomas [74–77]. In meningiomas, BRAF V600E mutation was reported in two cases of rhabdoid meningioma [78, 79], one of which improved after treatment with BRAF inhibitor [78]. However, this mutation is not detected in the other histological subtypes; three studies identified no BRAF V600E mutation in non-rhabdoid meningiomas [24, 75, 80]. The various cytogenetic alterations have been described, especially in association with progression and malignancy of meningiomas. Chromosome loss of 1p, 6q, 10p, 10q, 14q, and 18q are common in atypical and anaplastic meningiomas [81–86]. Especially, losses of 1p and 14q were frequently reported as an independent prognostic marker [87–89]. NDRG family member 2 (NDRG2) and Maternally expressed gene 3 (MEG3) were described as candidate genes on 14q11.2 and 14q32, respectively [90, 91]. Polysomy of chromosome 5, 13, and 20 was described in angiomatous meningioma [92]. In meningioma, angiomatous component and microcystic change frequently coexist, especially in cases with microvascular pattern [93]. Ketter et al. [94] described that one of the characteristics of Grade I meningiomas with hyperdiploidy was microcystic pattern with numerous blood vessels. In their article, trisomy 5, 12, 17, and 20 were common, while monosomy 22 was rarely observed in hyperdiploidy meningiomas [94]. However, gains of 5, 12q, 17q, and 20q as well as 1q, 9q, and 15q were also common in high grade meningioma. [83, 94], suggesting that polysomy of chromosome 5 and others is not specific for angiomatous meningioma. Progression to grade III meningiomas is also associated with loss of CDKN2A (p16INKa/p14ARF), and CDKN2B (p15INK4b) [95–97], all of which located at 9p21. These 123 alterations include homozygous deletions, mutations, and lack of expression [95]. Activated TERT promoter mutations were more recently identified in meningioma, associated with recurrence and malignant progression [98, 99]. The hotspot mutations were C228T and C250T [98], which were also identified in various tumors such as melanoma, urothelial carcinoma, hepatocellular carcinoma, glioblastoma, and oligodendroglioma [100–105]. These mutations generate de novo consensus binding motifs for E-twenty-six (ETS) transcription factors, leading the transcriptional activation of TERT by two to four folds [100, 101]. Goutagny et al. [98] identified these mutations in both meningiomas with and without NF2 loss/mutations. Sahm et al. [99] described that TERT promoter mutations were statistically significantly associated with shorter time to progression, suggesting the importance of the assessment of TERT promoter status as well as histological classification and grading for meningiomas. Two well-studied meningioma cell lines, CH-157MN and IOMM-Lee, also harbored the TERT C228T mutation [106]. Vision for histologically and genetically integrated diagnosis of meningiomas In the current WHO classification of the central nervous system (2016), combined histological-molecular classification termed integrated diagnosis is applied for the diagnosis of gliomas [19] because genotype is more significantly associated with prognosis than histology [107]. However, as described above, more detailed investigations about the correlation between genotype and prognosis are required to establish integrated diagnosis for meningioma. The surrogate markers are necessary for histologically and genetically integrated diagnosis. In gliomas, mutationspecific antibodies for IDH1 R132H are useful in the routine clinical management [108]. In meningioma, few surrogate markers for mutations were reported. Sahm et al. [109] described the strong up-regulation of SFRP1 expression in all meningiomas with AKT1 E17K. Brastianos et al. [21] demonstrated the strong immunoreactivity for GAB1 in meningiomas harboring SMO mutations, and STMN1 expression was observed in AKT1-mutated and SMO-mutated meningiomas [21]. The expression of Merlin, the product of NF2 gene, can also be assessed by immunohistochemistry [110, 111]. However, the sensitivity, specificity, and accuracy of the immunohistochemistry for genotyping of meningiomas remain unclear. If the genetic status including TERT promoter region is applied to the classification of meningiomas, the development of more useful surrogate markers is necessary. Brain Tumor Pathol Acknowledgments We thank Shigeru Yamaguchi for providing the radiological images of patients. References 1. Ostrom QT, Gittleman H, Fulop J et al (2015) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012. Neuro Oncol 17 Suppl 4:iv1–iv62 2. Kotecha RS, Pascoe EM, Rushing EJ et al (2011) Meningiomas in children and adolescents: a meta-analysis of individual patient data. Lancet Oncol 12:1229–1239 3. Ostrom QT, Gittleman H, Liao P et al (2014) CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2007–2011. Neuro Oncol 16 Suppl 4:iv1–63 4. Mawrin C, Perry A (2010) Pathological classification and molecular genetics of meningiomas. J Neurooncol 99:379–391 5. van Alkemade H, de Leau M, Dieleman EM et al (2012) Impaired survival and long-term neurological problems in benign meningioma. Neuro Oncol 14:658–666 6. Adeberg S, Hartmann C, Welzel T et al (2012) Long-term outcome after radiotherapy in patients with atypical and malignant meningiomas–clinical results in 85 patients treated in a single institution leading to optimized guidelines for early radiation therapy. Int J Radiat Oncol Biol Phys 83:859–864 7. Mark J, Levan G, Mitelman F (1972) Identification by fluorescence of the G chromosome lost in human meningomas. Hereditas 71:163–168 8. Mark J, Mitelman F, Levan G (1972) On the specificity of the G abnormality in human meningomas studied by the fluorescence technique. Acta Pathol Microbiol Scand A 80:812–820 9. Zankl H, Zang KD (1972) Cytological and cytogenetical studies on brain tumors. 4. Identification of the missing G chromosome in human meningiomas as no. 22 by fluorescence technique. Humangenetik 14:167–169 10. Fontaine B, Rouleau GA, Seizinger BR et al (1991) Molecular genetics of neurofibromatosis 2 and related tumors (acoustic neuroma and meningioma). Ann N Y Acad Sci 615:338–343 11. Rouleau GA, Merel P, Lutchman M et al (1993) Alteration in a new gene encoding a putative membrane-organizing protein causes neuro-fibromatosis type 2. Nature 363:515–521 12. Sanson M, Marineau C, Desmaze C et al (1993) Germline deletion in a neurofibromatosis type 2 kindred inactivates the NF2 gene and a candidate meningioma locus. Hum Mol Genet 2:1215–1220 13. Trofatter JA, MacCollin MM, Rutter JL et al (1993) A novel moesin-, ezrin-, radixin-like gene is a candidate for the neurofibromatosis 2 tumor suppressor. Cell 72:791–800 14. MacCollin M, Ramesh V, Jacoby LB et al (1994) Mutational analysis of patients with neurofibromatosis 2. Am J Hum Genet 55:314–320 15. Ruttledge MH, Sarrazin J, Rangaratnam S et al (1994) Evidence for the complete inactivation of the NF2 gene in the majority of sporadic meningiomas. Nat Genet 6:180–184 16. De Vitis LR, Tedde A, Vitelli F et al (1996) Screening for mutations in the neurofibromatosis type 2 (NF2) gene in sporadic meningiomas. Hum Genet 97:632–637 17. Clark VE, Erson-Omay EZ, Serin A et al (2013) Genomic analysis of non-NF2 meningiomas reveals mutations in TRAF7, KLF4, AKT1, and SMO. Science 339:1077–1080 18. Abedalthagafi M, Bi WL, Aizer AA et al (2016) Oncogenic PI3K mutations are as common as AKT1 and SMO mutations in meningioma. Neuro Oncol 18:649–655 19. Louis DN, Ohgaki H, Wiestler OD et al (2016) WHO classification of tumours of the central nervous system. Lyon, France 20. Yuzawa S, Nishihara H, Yamaguchi S et al (2016) Clinical impact of targeted amplicon sequencing for meningioma as a practical clinical-sequencing system. Mod Pathol 29:708–716 21. Brastianos PK, Horowitz PM, Santagata S et al (2013) Genomic sequencing of meningiomas identifies oncogenic SMO and AKT1 mutations. Nat Genet 45:285–289 22. Reuss DE, Piro RM, Jones DT et al (2013) Secretory meningiomas are defined by combined KLF4 K409Q and TRAF7 mutations. Acta Neuropathol 125:351–358 23. Pang JC, Chung NY, Chan NH et al (2006) Rare mutation of PIK3CA in meningiomas. Acta Neuropathol 111:284–285 24. Bujko M, Kober P, Tysarowski A et al (2014) EGFR, PIK3CA, KRAS and BRAF mutations in meningiomas. Oncol Lett 7:2019–2022 25. Bouwmeester T, Bauch A, Ruffner H et al (2004) A physical and functional map of the human TNF-alpha/NF-kappa B signal transduction pathway. Nat Cell Biol 6:97–105 26. Scudiero I, Zotti T, Ferravante A et al (2012) Tumor necrosis factor (TNF) receptor-associated factor 7 is required for TNFalpha-induced Jun NH2-terminal kinase activation and promotes cell death by regulating polyubiquitination and lysosomal degradation of c-FLIP protein. J Biol Chem 287:6053–6061 27. Wang L, Wang L, Zhang S et al (2013) Downregulation of ubiquitin E3 ligase TNF receptor-associated factor 7 leads to stabilization of p53 in breast cancer. Oncol Rep 29:283–287 28. Carpten JD, Faber AL, Horn C et al (2007) A transforming mutation in the pleckstrin homology domain of AKT1 in cancer. Nature 448:439–444 29. Kim MS, Jeong EG, Yoo NJ et al (2008) Mutational analysis of oncogenic AKT E17K mutation in common solid cancers and acute leukaemias. Br J Cancer 98:1533–1535 30. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A et al (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091 31. Bleeker FE, Felicioni L, Buttitta F et al (2008) AKT1(E17K) in human solid tumours. Oncogene 27:5648–5650 32. Shoji K, Oda K, Nakagawa S et al (2009) The oncogenic mutation in the pleckstrin homology domain of AKT1 in endometrial carcinomas. Br J Cancer 101:145–148 33. Askham JM, Platt F, Chambers PA et al (2010) AKT1 mutations in bladder cancer: identification of a novel oncogenic mutation that can co-operate with E17K. Oncogene 29:150–155 34. Beaver JA, Gustin JP, Yi KH et al (2013) PIK3CA and AKT1 mutations have distinct effects on sensitivity to targeted pathway inhibitors in an isogenic luminal breast cancer model system. Clin Cancer Res 19:5413–5422 35. Lindhurst MJ, Sapp JC, Teer JK et al (2011) A mosaic activating mutation in AKT1 associated with the Proteus syndrome. N Engl J Med 365:611–619 36. Cohen MM Jr (2005) Proteus syndrome: an update. Am J Med Genet C Semin Med Genet 137c:38–52 37. Takahashi K, Yamanaka S (2006) Induction of pluripotent stem cells from mouse embryonic and adult fibroblast cultures by defined factors. Cell 126:663–676 38. Tetreault MP, Yang Y, Katz JP (2013) Kruppel-like factors in cancer. Nat Rev Cancer 13:701–713 39. Zhao W, Hisamuddin IM, Nandan MO et al (2004) Identification of Kruppel-like factor 4 as a potential tumor suppressor gene in colorectal cancer. Oncogene 23:395–402 40. Zammarchi F, Morelli M, Menicagli M et al (2011) KLF4 is a novel candidate tumor suppressor gene in pancreatic ductal carcinoma. Am J Pathol 178:361–372 123 Brain Tumor Pathol 41. Yu T, Chen X, Zhang W et al (2016) KLF4 regulates adult lung tumor-initiating cells and represses K-Ras-mediated lung cancer. Cell Death Differ 23:207–215 42. Buttitta F, Felicioni L, Barassi F et al (2006) PIK3CA mutation and histological type in breast carcinoma: high frequency of mutations in lobular carcinoma. J Pathol 208:350–355 43. Qiu W, Schonleben F, Li X et al (2006) PIK3CA mutations in head and neck squamous cell carcinoma. Clin Cancer Res 12:1441–1446 44. Karakas B, Bachman KE, Park BH (2006) Mutation of the PIK3CA oncogene in human cancers. Br J Cancer 94:455–459 45. Oda K, Stokoe D, Taketani Y et al (2005) High frequency of coexistent mutations of PIK3CA and PTEN genes in endometrial carcinoma. Cancer Res 65:10669–10673 46. Campbell IG, Russell SE, Choong DY et al (2004) Mutation of the PIK3CA gene in ovarian and breast cancer. Cancer Res 64:7678–7681 47. Schonleben F, Qiu W, Ciau NT et al (2006) PIK3CA mutations in intraductal papillary mucinous neoplasm/carcinoma of the pancreas. Clin Cancer Res 12:3851–3855 48. Kang S, Bader AG, Vogt PK (2005) Phosphatidylinositol 3-kinase mutations identified in human cancer are oncogenic. Proc Natl Acad Sci USA 102:802–807 49. Ikenoue T, Kanai F, Hikiba Y et al (2005) Functional analysis of PIK3CA gene mutations in human colorectal cancer. Cancer Res 65:4562–4567 50. Reifenberger J, Wolter M, Weber RG et al (1998) Missense mutations in SMOH in sporadic basal cell carcinomas of the skin and primitive neuroectodermal tumors of the central nervous system. Cancer Res 58:1798–1803 51. Lam CW, Xie J, To KF et al (1999) A frequent activated smoothened mutation in sporadic basal cell carcinomas. Oncogene 18:833–836 52. Jones DT, Jager N, Kool M et al (2012) Dissecting the genomic complexity underlying medulloblastoma. Nature 488:100–105 53. Pugh TJ, Weeraratne SD, Archer TC et al (2012) Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations. Nature 488:106–110 54. Bacci C, Sestini R, Provenzano A et al (2010) Schwannomatosis associated with multiple meningiomas due to a familial SMARCB1 mutation. Neurogenetics 11:73–80 55. Christiaans I, Kenter SB, Brink HC et al (2011) Germline SMARCB1 mutation and somatic NF2 mutations in familial multiple meningiomas. J Med Genet 48:93–97 56. Melean G, Velasco A, Hernandez-Imaz E et al (2012) RNAbased analysis of two SMARCB1 mutations associated with familial schwannomatosis with meningiomas. Neurogenetics 13:267–274 57. Smith MJ, O’Sullivan J, Bhaskar SS et al (2013) Loss-offunction mutations in SMARCE1 cause an inherited disorder of multiple spinal meningiomas. Nat Genet 45:295–298 58. Smith MJ, Wallace AJ, Bennett C et al (2014) Germline SMARCE1 mutations predispose to both spinal and cranial clear cell meningiomas. J Pathol 234:436–440 59. Evans LT, Van Hoff J, Hickey WF et al (2015) SMARCE1 mutations in pediatric clear cell meningioma: case report. J Neurosurg Pediatr 16:296–300 60. Raffalli-Ebezant H, Rutherford SA, Stivaros S et al (2015) Pediatric intracranial clear cell meningioma associated with a germline mutation of SMARCE1: a novel case. Childs Nerv Syst 31:441–447 61. Gerkes EH, Fock JM, den Dunnen WF et al (2016) A heritable form of SMARCE1-related meningiomas with important implications for follow-up and family screening. Neurogenetics 17:83–89 123 62. Schmitz U, Mueller W, Weber M et al (2001) INI1 mutations in meningiomas at a potential hotspot in exon 9. Br J Cancer 84:199–201 63. Aavikko M, Li SP, Saarinen S et al (2012) Loss of SUFU function in familial multiple meningioma. Am J Hum Genet 91:520–526 64. Kijima C, Miyashita T, Suzuki M et al (2012) Two cases of nevoid basal cell carcinoma syndrome associated with meningioma caused by a PTCH1 or SUFU germline mutation. Fam Cancer 11:565–570 65. Wicking C, Smyth I, Bale A (1999) The hedgehog signalling pathway in tumorigenesis and development. Oncogene 18:7844–7851 66. Staal FJ, van der Luijt RB, Baert MR et al (2002) A novel germline mutation of PTEN associated with brain tumours of multiple lineages. Br J Cancer 86:1586–1591 67. Lyons CJ, Wilson CB, Horton JC (1993) Association between meningioma and Cowden’s disease. Neurology 43:1436–1437 68. De Moura J, Kavalec FL, Doghman M et al (2010) Heterozygous TP53stop146/R72P fibroblasts from a Li–Fraumeni syndrome patient with impaired response to DNA damage. Int J Oncol 36:983–990 69. Kanno H, Yamamoto I, Yoshida M et al (2003) Meningioma showing VHL gene inactivation in a patient with von Hippel– Lindau disease. Neurology 60:1197–1199 70. Nakamura Y, Shimizu T, Ohigashi Y et al (2005) Meningioma arising in Werner syndrome confirmed by mutation analysis. J Clin Neurosci 12:503–506 71. Leblanc R (2000) Familial adenomatous polyposis and benign intracranial tumors: a new variant of Gardner’s syndrome. Can J Neurol Sci 27:341–346 72. Igaz P (2009) MEN1 clinical background. Adv Exp Med Biol 668:1–15 73. Abdel-Rahman MH, Pilarski R, Cebulla CM et al (2011) Germline BAP1 mutation predisposes to uveal melanoma, lung adenocarcinoma, meningioma, and other cancers. J Med Genet 48:856–859 74. Dougherty MJ, Santi M, Brose MS et al (2010) Activating mutations in BRAF characterize a spectrum of pediatric lowgrade gliomas. Neuro Oncol 12:621–630 75. Schindler G, Capper D, Meyer J et al (2011) Analysis of BRAF V600E mutation in 1,320 nervous system tumors reveals high mutation frequencies in pleomorphic xanthoastrocytoma, ganglioglioma and extra-cerebellar pilocytic astrocytoma. Acta Neuropathol 121:397–405 76. Kleinschmidt-DeMasters BK, Aisner DL, Birks DK et al (2013) Epithelioid GBMs show a high percentage of BRAF V600E mutation. Am J Surg Pathol 37:685–698 77. Sugimoto K, Ideguchi M, Kimura T et al (2016) Epithelioid/ rhabdoid glioblastoma: a highly aggressive subtype of glioblastoma. Brain Tumor Pathol 33:137–146 78. Mordechai O, Postovsky S, Vlodavsky E et al (2015) Metastatic rhabdoid meningioma with BRAF V600E mutation and good response to personalized therapy: case report and review of the literature. Pediatr Hematol Oncol 32:207–211 79. Behling F, Barrantes-Freer A, Skardelly M et al (2016) Frequency of BRAF V600E mutations in 969 central nervous system neoplasms. Diagn Pathol 11:55 80. Forest F, Yvorel V, Vassal F et al (2015) BRAF V600 point mutation is not present in relapsing meningioma. Clin Neuropathol 34:164–165 81. Bello MJ, de Campos JM, Kusak ME et al (1994) Allelic loss at 1p is associated with tumor progression of meningiomas. Genes Chromosomes Cancer 9:296–298 Brain Tumor Pathol 82. Simon M, von Deimling A, Larson JJ et al (1995) Allelic losses on chromosomes 14, 10, and 1 in atypical and malignant meningiomas: a genetic model of meningioma progression. Cancer Res 55:4696–4701 83. Weber RG, Bostrom J, Wolter M et al (1997) Analysis of genomic alterations in benign, atypical, and anaplastic meningiomas: toward a genetic model of meningioma progression. Proc Natl Acad Sci USA 94:14719–14724 84. Lamszus K, Kluwe L, Matschke J et al (1999) Allelic losses at 1p, 9q, 10q, 14q, and 22q in the progression of aggressive meningiomas and undifferentiated meningeal sarcomas. Cancer Genet Cytogenet 110:103–110 85. Cai DX, Banerjee R, Scheithauer BW et al (2001) Chromosome 1p and 14q FISH analysis in clinicopathologic subsets of meningioma: diagnostic and prognostic implications. J Neuropathol Exp Neurol 60:628–636 86. Aizer AA, Abedalthagafi M, Bi WL et al (2016) A prognostic cytogenetic scoring system to guide the adjuvant management of patients with atypical meningioma. Neuro Oncol 18:269–274 87. Sulman EP, Dumanski JP, White PS et al (1998) Identification of a consistent region of allelic loss on 1p32 in meningiomas: correlation with increased morbidity. Cancer Res 58:3226–3230 88. Tabernero MD, Espinosa AB, Maillo A et al (2005) Characterization of chromosome 14 abnormalities by interphase in situ hybridization and comparative genomic hybridization in 124 meningiomas: correlation with clinical, histopathologic, and prognostic features. Am J Clin Pathol 123:744–751 89. Linsler S, Kraemer D, Driess C et al (2014) Molecular biological determinations of meningioma progression and recurrence. PLoS One 9:e94987 90. Lusis EA, Watson MA, Chicoine MR et al (2005) Integrative genomic analysis identifies NDRG2 as a candidate tumor suppressor gene frequently inactivated in clinically aggressive meningioma. Cancer Res 65:7121–7126 91. Zhang X, Gejman R, Mahta A et al (2010) Maternally expressed gene 3, an imprinted noncoding RNA gene, is associated with meningioma pathogenesis and progression. Cancer Res 70:2350–2358 92. Abedalthagafi MS, Merrill PH, Bi WL et al (2014) Angiomatous meningiomas have a distinct genetic profile with multiple chromosomal polysomies including polysomy of chromosome 5. Oncotarget 5:10596–10606 93. Hasselblatt M, Nolte KW, Paulus W (2004) Angiomatous meningioma: a clinicopathologic study of 38 cases. Am J Surg Pathol 28:390–393 94. Ketter R, Kim YJ, Storck S et al (2007) Hyperdiploidy defines a distinct cytogenetic entity of meningiomas. J Neurooncol 83:213–221 95. Bostrom J, Meyer-Puttlitz B, Wolter M et al (2001) Alterations of the tumor suppressor genes CDKN2A (p16(INK4a)), p14(ARF), CDKN2B (p15(INK4b)), and CDKN2C (p18(INK4c)) in atypical and anaplastic meningiomas. Am J Pathol 159:661–669 96. Simon M, Park TW, Koster G et al (2001) Alterations of INK4a(p16-p14ARF)/INK4b(p15) expression and telomerase activation in meningioma progression. J Neurooncol 55:149–158 97. Perry A, Banerjee R, Lohse CM et al (2002) A role for chromosome 9p21 deletions in the malignant progression of meningiomas and the prognosis of anaplastic meningiomas. Brain Pathol 12:183–190 98. Goutagny S, Nault JC, Mallet M et al (2014) High incidence of activating TERT promoter mutations in meningiomas undergoing malignant progression. Brain Pathol 24:184–189 99. Sahm F, Schrimpf D, Olar A et al (2016) TERT promoter mutations and risk of recurrence in meningioma. J Natl Cancer Inst 108 100. Huang FW, Hodis E, Xu MJ et al (2013) Highly recurrent TERT promoter mutations in human melanoma. Science 339:957–959 101. Horn S, Figl A, Rachakonda PS et al (2013) TERT promoter mutations in familial and sporadic melanoma. Science 339:959–961 102. Rachakonda PS, Hosen I, de Verdier PJ et al (2013) TERT promoter mutations in bladder cancer affect patient survival and disease recurrence through modification by a common polymorphism. Proc Natl Acad Sci USA 110:17426–17431 103. Huang DS, Wang Z, He XJ et al (2015) Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer 51:969–976 104. Reuss DE, Kratz A, Sahm F et al (2015) Adult IDH wild type astrocytomas biologically and clinically resolve into other tumor entities. Acta Neuropathol 130:407–417 105. Brat DJ, Verhaak RG, Aldape KD et al (2015) Comprehensive, integrative genomic analysis of diffuse lower-grade gliomas. N Engl J Med 372:2481–2498 106. Johanns TM, Fu Y, Kobayashi DK et al (2016) High incidence of TERT mutation in brain tumor cell lines. Brain Tumor Pathol 33:222–227 107. Suzuki H, Aoki K, Chiba K et al (2015) Mutational landscape and clonal architecture in grade II and III gliomas. Nat Genet 47:458–468 108. Kato Y (2015) Specific monoclonal antibodies against IDH1/2 mutations as diagnostic tools for gliomas. Brain Tumor Pathol 32:3–11 109. Sahm F, Bissel J, Koelsche C et al (2013) AKT1E17K mutations cluster with meningothelial and transitional meningiomas and can be detected by SFRP1 immunohistochemistry. Acta Neuropathol 126:757–762 110. Buccoliero AM, Gheri CF, Castiglione F et al (2007) Merlin expression in secretory meningiomas: evidence of an NF2-independent pathogenesis? Immunohistochemical study. Appl Immunohistochem Mol Morphol 15:353–357 111. Pavelin S, Becic K, Forempoher G et al (2014) The significance of immunohistochemical expression of merlin, Ki-67, and p53 in meningiomas. Appl Immunohistochem Mol Morphol 22:46–49 123