NcXHF

MAWRIN, CHUNG, AND PREUSSER
Fibroblastic, transitional, and psammomatous have higher
frequencies of NF2 alterations than meningothelial or secretory
meningiomas. 28,31-33 Accordingly, patients with non-
NF2 familial multiple meningiomas are more likely to
develop meningothelial tumors. 34 An association between
the NF2 gene and location has also been reported, and
tumors of the convexity are more likely than anterior cranialbased
tumors to harbor NF2 alterations. 11 In contrast, patients
with neurofıbromatosis type 1 (NF1) only rarely
present with meningiomas, 35 and NF1 gene mutations are
absent in anaplastic meningiomas, which suggests that NF1
alterations are not involved in meningioma development
and/or progression. 30
Based on the clearly established role of NF2, it could be
demonstrated that NF2 inactivation in leptomeningeal cells
of conditional NF2 knockout mice (NF2 flox/flox ) by Cre recombinase
injection induces meningiomas. 36 Most of these
mouse tumors recapitulate the meningothelial, fıbroblastic,
or transitional subtype of human meningiomas and are characterized
by reduced merlin expression. The knowledge concerning
the mechanisms driving the development of the
main histopathologic subtypes among grade 1 meningiomas
has been expanded recently by generating a mouse model
with inactivation of meningeal NF2 by using the prostaglandin
D2 synthase (PGDS) gene promoter. PGDS is a specifıc
marker of arachnoidal cells. 37 NF2 inactivation in PDGSpositive
meningeal progenitor cells resulted in both meningothelial
and fıbroblastic meningiomas. 38 Of note, NF2
inactivation in mice led to meningioma development only
during a critical prenatal and perinatal time frame.
On the basis of recent whole genome-sequencing approaches,
few other recurrent genetic alterations have been
identifıed recently in benign meningiomas. In 2013, four
genes altered in a small fraction of meningiomas—TRAF7,
KLF4, AKT1, and SMO—were identifıed. 29,39,40 Probably the
most important new mutation identifıed is related to the
v-akt murine thymoma viral oncogene homolog 1 gene
(AKT1), with a hotspot mutation (p.Glu17Lys) named
AKT1 E17K . This somatic mutation occurs in breast, ovarian,
and colorectal cancers. 41,42 In meningioma, this mutation
was found nearly exclusively in 7% to 12% of WHO grade 1
meningiomas but was (exceptionally) rare in grade 2 and was
absent in grade 3 tumors. 39,40 The AKT1 E17K mutation was
found predominantly in the meningothelial/transitional
subtypes, and tumors that harbored the AKT1 E17K mutation
were NF2 wild type. Another gene found mutated in grade 1
meningiomas was the receptor-associated factor 7 gene
(TRAF7). 39 TRAF7 is located on chromosome 16p13 and encodes
a proapoptotic protein that interacts with multiple signaling
pathways. TRAF7 mutations are mutually exclusive of
NF2 mutations and occur in approximately 24% of meningiomas.
39 They are present in 93% to 100% of secretory meningiomas.
43 In addition, meningiomas with TRAF7 mutations
are almost always characterized by the mutation K409Q in
the gene for the transcription factor Kruppel-like factor 4
(KLF4). KLF4, located on chromosome 9q, is involved in
transcriptional activation and repression. 44 The combined
TRAF7/KLF4 mutation characterizes secretory meningiomas
39,43 and provides a molecular marker for this grade 1
subtype. Meningiomas with TRAF7/KLF4 mutations are predominantly
located at the medial/lateral skull base.
Another non–NF2-associated mutation of skull base meningiomas
affects the Smoothened gene, SMO. SMO mutations
occur in 4% to 5% of grade 1 meningiomas and are
restricted to the medial anterior skull base near the midline.
SMO mutations are exclusive of NF2 and of AKT1 or TRAF7/
KLF4. 29,39
Although all of these mutations are mutually exclusive of
NF2 alterations, other genetic alterations occur in association
with chromosome 22 in meningiomas. One gene located on
chromosome is SMARCB1, and alterations are frequently
found in SMARCB1 in pediatric malignant rhabdoid tumors.
Screening a large group of sporadic meningiomas revealed
that SMARCB1 mutations occur with low frequency and
might be cooperating with NF2 mutations, because tumors
showing both SMACRB1 and NF2 mutations were reported.
45,46 SMARCB1-mutated meningiomas are preferentially
found at the falx cerebri. 47
In families with multiple spinal meningiomas and without
NF2 mutations, a loss-of-function mutation in the SMARCE1
gene was recently identifıed. 48 SMARCE1 is located on chromosome
17q21 and encodes for a 57-kDa subunit of the SWI/SNF
complex, which is involved in the regulation of chromatin structure
by nucleosome remodeling. The mutation occurs selectively
in spinal meningiomas with histologic features of clear cell
meningioma, so it providing a potential molecular hallmark for
this rare meningioma subtype.
The merlin protein belongs to the protein 4.1 family, with
members linking the membrane protein to the cytoskeleton.
One gene of the protein 4.1 family relevant for meningioma
biology is DAL1. Reduced expression of the DAL1 gene product
protein 4.1B was found in approximately 60% of meningiomas
regardless of histologic grade, which suggests that
protein 4.1B loss is another early event in meningioma
pathogenesis. 49,50 Nearly all tumors with DAL1 LOH have simultaneous
NF2 LOH. 51 Mice lacking DAL1 do not develop
tumors, 52 which suggests that DAL1 alterations are early progression–associated
steps. In patients with multiple meningiomas,
DAL1 mutations were found in both tumor and
paired blood samples, which suggests substantial differences
between patients with sporadic single and multiple meningioma
with respect to DAL1. 34
MALIGNANT PROGRESSION IN MENINGIOMA
Meningiomas are generally thought to progress from lowgrade
to high-grade tumors. Histologically, progression
from grade 1 to grade 2 can be confırmed in 17% to 38% and
from grade 1/2 to grade 3 in 54% to 70%. 53,54 At the cytogenetic
level, a stepwise acquisition of chromosomal gains and
losses during meningioma progression has been proven.
Losses of 1p, 6q, 10q, 14q, and 18q, as well as gains of 1q, 9q,
12q, 15q, 17q, and 20q have been proposed as important
events in meningioma progression and recurrence, 29,55-59
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