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Genetic landscape of meningioma

Brain Tumor Pathol
DOI 10.1007/s10014-016-0271-7
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
Department of Diagnostic Pathology, Asahikawa Medical
University, 2-1-1-1 Midorigaoka Higashi, Asahikawa,
Hokkaido 078-8510, Japan
Department of Cancer Pathology, Hokkaido University
Graduate School of Medicine, Sapporo, Japan
Department of Translational Pathology, Hokkaido University
Graduate School of Medicine, Sapporo, Japan
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
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
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
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
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
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
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
NF2 (53%)
None (20%)
NF2 loss
296/553 (54%)
NF2 mut
203/553 (37%)
111/553 (20%)
52/553 (9%)
49/553 (9%)
9/200 (4.5%)
18/553 (3%)
595 aa
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
480 aa
1068 aa
787 aa
Missense mutation
Frameshift mutation
Nonsense mutation
Splice-site mutation
Inframe In/del
Silent mutation
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.
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].
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 %).
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
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.
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.
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
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
(n = 339)
(n = 56)
(n = 34)
(n = 17)
(n = 57)
(n = 10)
57 (35–88)
52 (35–79)
55.5 (28–73)
53 (18–79)
56 (45–86)
(n = 124)
Median (range)
58 (15–89)
54 (23–90)
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 %)
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 %)
8 (2 %)
0 (0 %)
1 (3 %)
0 (0 %)
2 (4 %)
0 (0 %)
0 (0 %)
8 (2 %)
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
1 (1 %)
3 (1 %)
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
Middle fossa, unknown
10 (3 %)
2 (4 %)
0 (0 %)
0 (0 %)
0 (0 %)
0 (0 %)
4 (3 %)
1 (0 %)
10 (18 %)
0 (0 %)
0 (0 %)
4 (7 %)
3 (30 %)
1 (1 %)
29 (9 %)
24 (43 %)
17 (50 %)
11 (65 %)
21 (37 %)
2 (20 %)
42 (34 %)
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 %)
0 (0 %)
1 (2 %)
0 (0 %)
0 (0 %)
1 (2 %)
0 (0 %)
1 (1 %)
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 %)
99 (29 %)
0 (0 %)
2 (6 %)
0 (0 %)
2 (4 %)
0 (0 %)
16 (13 %)
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 %)
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 %)
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 %)
10 (3 %)
0 (0 %)
1 (3 %)
0 (0 %)
2 (4 %)
0 (0 %)
4 (3 %)
WHO grade
77 (23 %)
3 (5 %)
3 (9 %)
1 (6 %)
4 (7 %)
0 (0 %)
13 (10 %)
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 %)
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
Some cases showed more than two histological subtypes
Brain Tumor Pathol
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
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
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
Grade I
(ex. Chr 5 trisomy)
Grade II
(Clear cell)
Grade III
Loss of 1p, 6q, 10, 14q, 18q
Gain of 1q, 9q, 12q, 15q, 17q, 20q
CDKN2A/2B (Loss of 9p21)
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.
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
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
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
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.
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