Genetic landscape of meningioma

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
ysayaka528@asahikawa-med.ac.jp
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