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From the Departments of Neurosurgery*
and
Neuropathology,
University of Bonn Medical
Center, Bonn, Germany; the Department of
Neuropathology,
Heinrich-Heine-University,
Düsseldorf, Germany; the Institute of Human
Genetics,
Ruprecht-Karls-University,
Heidelberg, Germany; the Department Organization of Complex
Genomes,¶
German Cancer Research Center,
Heidelberg, Germany; and the Department of Pathology,||
Division of Molecular Histopathology, Addenbrooke’s Hospital,
Cambridge, United Kingdom
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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6 per 100,000 population.1
Most
meningiomas are slowly growing benign tumors that histologically
correspond to grade I of the World Health Organization’s
classification of tumors of the nervous system.1
Atypical
meningiomas (World Health Organization grade II) are a histologically
defined subgroup of meningiomas that are associated with a
significantly higher risk of local tumor recurrence than benign
meningiomas, even after gross total resection.1
Approximately 2 to 3% of all meningiomas show histological features of
malignancy and are therefore classified as anaplastic meningiomas
(World Health Organization grade III).1
Anaplastic
meningiomas are associated with a poor prognosis, as indicated by a
median survival time of <2 years after diagnosis.2 The most common genetic alteration in meningiomas is loss of heterozygosity (LOH) at polymorphic markers on 22q, which has been detected in 40 to 70% of all meningiomas.3,4 LOH on 22q is typically associated with mutation, deletion, and/or loss of expression of the neurofibromatosis type 2 gene (NF2) at 22q12.2.5-7 NF2 alterations have been detected in >50% of sporadic meningiomas of all malignancy grades, indicating that inactivation of the NF2 gene product merlin/schwannomin represents an important early event in meningioma development.5-7
We have previously shown by comparative genomic hybridization (CGH) and molecular genetic analyses that atypical and anaplastic meningiomas demonstrate an accumulation of multiple genomic abnormalities in addition to NF2 alterations and LOH on 22q.8 The most common additional aberration, which was detected in more than two-thirds of atypical and anaplastic meningiomas, was the loss of genetic material from the short arm of chromosome 1. In addition, losses on 9p were frequently found in anaplastic meningiomas but only rarely in atypical and benign meningiomas. Preliminary analysis of the CDKN2A gene at 9p21 indicated that >20% of anaplastic meningiomas had homozygously lost this gene.8 CDKN2A encodes the p16INK4a protein, which functions as regulator of G1/S-phase transition by inhibiting the activity of cyclin-dependent kinases Cdk4 and Cdk6.9 The p14ARF protein is transcribed from a unique exon 1ß and exons 2 and 3 of CDKN2A using an alternative reading frame.9 Transcription of the p14ARF gene is regulated independently from CDKN2A by a distinct promotor.9,10 The product of p14ARF regulates the activity of the p53 tumor suppressor protein by binding to Mdm2 and inhibiting Mdm2-mediated degradation of p53.10 CDKN2A belongs to a family of genes coding for structurally related inhibitors of cyclin-dependent kinases that are important in cell-cycle regulation at the G1/S-phase transition.9 Other members of this family are CDKN2B at 9p21 (encoding p15INK4b), CDKN2C at 1p32 (encoding p18INK4c), and CDKN2D at 19q13 (encoding p19INK4d).9 CDKN2A and CDKN2B are well-known tumor suppressor genes that are frequently aberrant in various types of human tumors. Mutation of the CDKN2C gene has also been reported in human tumors, albeit at much lower frequency.11-13
We have now investigated 67 meningiomas of all World Health Organization grades for deletion, mutation, and expression of the CDKN2A, p14ARF, CDKN2B, and CDKN2C genes. All tumors were additionally investigated for amplification of the MDM2 and CDK4 genes and for mutation of the TP53 gene. Our data indicate that CDKN2C is rarely altered in meningiomas and, therefore, does not represent the major target of the frequent losses on 1p in atypical and anaplastic meningiomas. However, the majority of anaplastic meningiomas shows aberrations of the CDKN2A, p14ARF, and CDKN2B genes.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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We investigated meningiomas from 67 patients (26 male, 41 female;
mean age at operation, 61 years; range, 6 to 90 years). All tumors were
histologically reclassified according to the third edition of the World
Health Organization classification of tumors of the nervous
system.1
Seven tumors from our previous
series,8
which were originally classified as anaplastic
meningioma, had to be reclassified as atypical meningioma. The main
reasons for the reclassification were that the mitotic count was <20
mitoses per 10 high-power fields and that brain invasion is no longer
regarded as a histological marker of malignancy. The present tumor
series thus included 20 benign meningiomas (World Health Organization
grade I), 34 atypical meningiomas (World Health Organization grade II),
and 13 anaplastic meningiomas (World Health Organization grade III)
(Table 1)
. Forty-three tumors were
primary tumors and 24 tumors were recurrences. One case was a spinal
metastasis of an intracranial anaplastic meningioma. None of the
primary and only one of the recurrent tumors had been treated by
irradiation before operation. Parts of each tumor were snap-frozen
immediately after operation and stored at -80°C. Extraction of
high-molecular weight DNA and RNA from frozen tumor tissue was
performed by ultracentrifugation as described elsewhere.14
Peripheral blood samples for the extraction of constitutive (leukocyte)
DNA were available from 53 patients.
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Fifty-five of the meningiomas had been previously investigated for chromosomal imbalances by CGH.8 Five tumors were additionally analyzed by CGH using the same protocol. All 53 tumors for which corresponding leukocyte DNA was available were evaluated for LOH at the following microsatellite markers: D1S224 (1p22), D1S496 (1p34), D1S468 (1p36), D9S171 (9p21, proximal to CDKN2A, p14ARF, and CDKN2B), D9S157 (9p21, distal to CDKN2A, p14ARF, and CDKN2B), and D9S168 (9p22-23). Polymerase chain reaction (PCR) amplification and assessment for allelic loss was performed as described.15 LOH results of 40 tumors had been reported on previously.8
Single-Strand Conformation Polymorphism (SSCP)/Heteroduplex Analysis
The mutation analyses of CDKN2A and
p14ARF (exon 1
, exon 1ß, exons 2 and
3), CDKN2B (exons 1 and 2), and CDKN2C (exons 2
and 3) were performed by a combined SSCP/heteroduplex
analysis.16
The oligonucleotide primer sequences used for
amplification of the individual exons of these genes are summarized in
Table 2
. All tumors were additionally
analyzed for mutations in exons 5 to 8 of the TP53 tumor
suppressor gene.16
PCR products spanning CDKN2C
exon 3 and CDKN2A exon 2 were cut with restriction enzymes
(AluI and SmaI, respectively) before
SSCP/heteroduplex analysis. PCR products showing aberrant
SSCP/heteroduplex band patterns were sequenced in both directions using
the BigDye cycle sequencing kit (Applied Biosystems, Foster City, CA)
and an ABI PRISM 377 semiautomated DNA sequencer (Applied Biosystems).
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All tumors were screened by duplex-PCR analysis for homozygous
deletions of CDKN2A, p14ARF,
CDKN2B, and CDKN2C, as well as for amplification
of CDK4 and MDM2 as described.13,17
The individual PCR products were separated on 3% agarose gels and
ethidium bromide-stained fragments were recorded by the Gel-Doc 1000
system (Bio-Rad, Hercules, CA). Quantitative analysis of the signal
intensities obtained for the target gene and the reference gene was
performed with the Molecular Analyst software (version 2.1, Bio-Rad).
Tumors showing evidence for homozygous deletion of CDKN2A,
p14ARF, and CDKN2B by
duplex-PCR were additionally analyzed by Southern blot analysis. For
Southern blot analysis, 2.5 µg of DNA were digested with the
restriction enzyme TaqI, electrophoretically separated on
0.8% agarose gels, and alkali-blotted to
Hybond-N+ membranes (Amersham-Pharmacia Biotech,
Freiburg, Germany). The membranes were sequentially hybridized with
-[32P]-dCTP-labeled, PCR-generated probes
for CDKN2A (exon 1), p14ARF
(exon 1ß), CDKN2B (exon 1), and the reference locus
D2S44 (pYNH24, obtained from American Type Culture
Collection, Rockville, MD). Hybridized membranes were exposed to
imaging plates (Fuji, Kanagawa, Japan) and analyzed using the FLA-2000
Phosphor and Fluorescent image analyzer (Fuji). Quantitative
densitometric analysis of the gene copy number was performed with the
Mac BAS version 2.5 software (Image Reader, version 1.4E, and Image
Gauge, version 3.0) as described.18
Expression Analyses
For expression analyses at the mRNA level, 3 µg of total RNA
from each tumor were reverse-transcribed into cDNA in a total volume of
50 µl using random hexanucleotide primers and Superscript reverse
transcriptase (Gibco BRL, Eggenstein, Germany). Expression of
CDKN2A, p14ARF, and
CDKN2B was determined by duplex reverse transcription-PCR,
using ß-2-microglobulin (B2M) mRNA for reference (primer sequences
are listed in Table 2
). Duplex reverse transcription-PCR for
CDKN2C mRNA expression was performed according to Husemann
and colleagues.13
As reference tissue, we used
leptomeningeal tissue samples obtained at autopsy and nonneoplastic
brain tissue (cortex and white matter from the temporal lobe) from a
patient operated on for chronic epilepsy. PCR products were separated
on 2% agarose gels, and ethidium bromide-stained bands were recorded
by the Gel-Doc 1000 system.
Bisulfite Sequencing
Those tumors that lacked detectable transcripts from either
CDKN2A, p14ARF, or
CDKN2B but showed neither mutations nor homozygous deletions
of these genes were analyzed for hypermethylation of the CpG islands
within the first exons of these genes. Genomic DNA (1 µg) was treated
with sodium bisulfite as described by Herman and
colleagues.19
PCR analyses were performed with 70 to 80 ng
of the bisulfite-modified DNA as template using 0.625 U of HotStar
Taq DNA polymerase (Qiagen, Hilden, Germany) in 1x Qiagen
PCR-buffer with 0.2 mmol/L of each dNTP and 0.5 µmol/L of each primer
(Table 2)
under the following PCR conditions: 15 minutes initial
denaturation at 95°C were followed by 40 cycles of 30 seconds at
94°C, 30 seconds at the appropriate Tm value
for each primer pair, 90 seconds at 72°C, and a final extension of 5
minutes. In the case of p14ARF and
CDKN2B, a second round of PCR was performed using 1 µl of
the previous PCR reaction as template and nested forward primers in
combination with original reverse primers (Table 2)
. The
re-amplification was done for 35 cycles under the same PCR conditions
as described above. The PCR products were purified with the Jetquick
gel extraction spin kit (Genomed, Bad Oeynhausen, Germany), subjected
to cycle sequencing with the BigDye cycle sequencing kit and analyzed
on an ABI PRISM 377 semiautomated DNA sequencer.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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provides an overview of the 67 meningiomas investigated,
including selected clinical data of the patients, histopathological
diagnoses, and molecular genetic findings. Losses of genetic material
from 1p were found in 11 of 13 anaplastic meningiomas (85%), 23 of 34
atypical meningiomas (68%), and 5 of 20 benign meningiomas (25%). The
region of common loss on 1p mapped to 1p34-pter, distal to the marker
D1S468, a finding in line with our previous study on a
smaller series of cases.15
Duplex-PCR analysis of CDKN2C (exon 2) showed no homozygous
deletion. Mutation analysis identified one atypical meningioma (MN56B)
that carried a somatic CDKN2C nonsense mutation (c.202C>T:
R68X) (Figure 1b)
. CGH analysis of tumor
MN56B revealed loss of 1p and microsatellite analysis showed LOH at all
informative loci on 1p, indicating complete loss of wild-type
CDKN2C in MN56B (Figure 1a)
. None of 59 meningiomas
investigated by duplex reverse transcription-PCR lacked detectable
CDKN2C transcripts (Table 1)
.
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. Eleven tumors demonstrated losses that
included chromosome band 9p21 where CDKN2A,
p14ARF, and CDKN2B are located.
One anaplastic meningioma (MN34) showed LOH at the D9S168
locus (9p22-p23) but retention of heterozygosity at D9S157
and D9S171, both located at 9p21 (Figure 2)
. CGH analysis indicated loss
restricted to 9p24 in this tumor.8
Nevertheless, MN34
showed loss of one copy of CDKN2A,
p14ARF, and CDKN2B by
duplex-PCR and Southern blot analysis. We therefore investigated MN34
for LOH at three additional microsatellite markers located at 9p21
between D9S157 and D1S171
(D9S974, D9S942, D9S1748).
These loci demonstrated loss of one allele in MN34 (Figure 2)
. Taken
together, these findings indicate a complex rearrangement of 9p in
MN34, which resulted in interstitial and terminal losses of 9p
sequences. Tumors MN31 and MN73 were previously reported to demonstrate
LOH at D9S168.8
However, re-analysis of these
two cases did not confirm this finding and CGH analysis also showed no
losses on 9p in these cases.8
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; Table 1
). Mutation
analysis of CDKN2A, p14ARF, and
CDKN2B identified somatic point mutations within exon 2 of
CDKN2A and p14ARF in the
anaplastic meningiomas MN34 and MN63B (Figure 1, c and d)
. The mutation
detected in MN34 results in a premature stop of translation at position
88 of p16INK4a (c.262G>T: E88X). The same
mutation causes a single amino-acid exchange at codon 102 of
p14ARF (c.305G>T: G102V). MN63B carried a point
mutation predicting single amino-acid exchanges in
p16INK4a (c.262G>A; E88K) and
p14ARF (c.305G>A; G102E) (Figure 1, c and d)
.
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, Table 1
). These five
tumors were investigated by bisulfite sequencing of the CpG islands
within the first exons of CDKN2A,
p14ARF, and CDKN2B. The
atypical meningioma MN61 demonstrated CpG island hypermethylation of
all three genes (Figure 5)
. The other
four tumors showed no 5'-CpG island hypermethylation of these genes.
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. No amplification of CDK4 and/or
MDM2 was detected in the remaining 66 meningiomas
investigated. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Several studies indicated that losses of 1p are of particular importance in the pathogenesis of atypical and anaplastic meningiomas.8,22,24,25 We found 1p losses in 85% of the anaplastic meningiomas and 68% of the atypical meningiomas, but only 25% of the benign meningiomas of our series. We previously mapped a candidate tumor suppressor region to 1p34-pter, distally to the anonymous locus D1S496.15 This region includes the chromosomal segment 1p36 that is commonly deleted in diverse human tumor types, including neuroblastoma, malignant melanoma, oligodendroglioma, and different carcinomas.13,26 The present tumor series included 35 cases from our previous study. Microsatellite analysis of the 22 newly analyzed tumors did not further narrow down the candidate gene region at 1p34-pter. However, because only three microsatellite loci from 1p were analyzed, we may have missed cases with small deletions. Another group reported on a meningioma-associated tumor suppressor gene region that is located closer to the centromere, ie, that maps to 1p32 between D1S2713 and D1S2134.27
To date, only a few candidate genes from 1p have been evaluated for tumor-associated alterations in meningiomas. One study suggested that the alkaline phosphatase gene (ALPL) at 1p34-p36.1 is a meningioma suppressor gene because its expression was found to be down-regulated in the majority of meningiomas with loss of 1p.25 However, structural ALPL alterations have not been documented in meningiomas so far and functional evidence for tumor suppressor properties of its gene product is lacking. Analysis of the hRAD54 gene (1p32) revealed no mutations in a series of 29 meningiomas with 1p deletions.28 We investigated the CDKN2C gene at 1p32 for mutation and expression in meningiomas. This gene maps outside of the regions of common deletion identified by LOH analyses.15,27 Nevertheless, the 1p losses detected in 37 of 39 meningiomas from our present tumor series included the CDKN2C locus at 1p32. CDKN2C codes for an 18-kd protein (p18INK4c) that binds to Cdk6 and Cdk4 and inhibits their kinase activity.29 Overexpression of p18INK4c in vivo inhibits cell proliferation and growth in a pRb-dependent manner.29 Point mutations or homozygous deletions of CDKN2C have been detected in small fractions of different tumor types, including breast carcinomas,11 acute lymphoblastic leukemias,30 multiple myelomas,31 and anaplastic oligodendrogliomas.13 We found a novel CDKN2C nonsense mutation (c.202C>T: R68X) in an atypical meningioma. This mutation results in a truncated protein lacking three of the five ankyrin repeats that are important for the correct tertiary structure and stability of the protein.32 In addition, the truncated protein has lost its binding sites for Cdk4 and Cdk6 and thus can no longer inhibit the activity of these proteins.33 The absence of detectable CDKN2C alterations in 66 of 67 meningiomas studied and the presence of CDKN2C transcripts in all tumors investigated by reverse transcription-PCR, however, indicate that this gene is not the major target of the common 1p losses in meningiomas. In line with our results, a recent study on 40 meningiomas identified only a single tumor with a homozygous deletion of the CDKN2C locus.34 The remaining 39 meningiomas neither showed CDKN2C point mutations nor loss of expression.
The CDKN2A, p14ARF, and CDKN2B genes at 9p21 are well-known tumor suppressor genes that are inactivated at high frequency in a large variety of human tumors.9 We found homozygous deletions including all three genes in 46% of anaplastic meningiomas, 3% of atypical meningiomas, but none of 20 benign meningiomas. Two additional anaplastic meningiomas carried CDKN2A and p14ARF point mutations. Our data seem to be at variance with other studies reporting that CDKN2A alterations are either rare35 or absent in meningiomas.36,37 However, these studies were based on small tumor series (generally <30 meningiomas), which mostly consisted of benign meningiomas of World Health Organization grade I. According to our data, alterations of CDKN2A, p14ARF, and CDKN2B are predominantly found in anaplastic meningiomas. Thus, the discrepant results between our study and former reports are likely because of the higher fraction of anaplastic meningiomas in our series.
We identified two anaplastic meningiomas with point mutations in exon 2 of CDKN2A. One of these mutations (c.262G>T: E88X) predicts a truncated p16INK4a protein, which is functionally impaired because it lacks parts of ankyrin repeat 3 and 4 as well as important residues for the interaction with Cdk4 and Cdk6.38,39 The second mutation detected (c.262G>A; E88K) maps to a site implicated in the binding of p16INK4a to Cdk4 and Cdk639 and thus likely results in a functional impairment of the protein. The significance of these mutations is supported by the fact that both have been repeatedly found as somatic alterations in different types of human tumors.9 In addition to an effect on p16INK4a, both mutations also result in missense mutations of p14ARF. Recent studies indicated that the C-terminal domain encoded by exon 2 of p14ARF contains an important nucleolar localization signal.40, 41 Mutations in exon 2 may therefore disrupt the nucleolar localization of p14ARF and thereby interfere with p14ARF-regulated Mdm2-dependent stabilization of p53.40,41
Transcriptional silencing by CpG methylation of 5'-regulatory sequences represents an epigenetic mechanism for the inactivation of various tumor suppressor genes, including the CDKN2A, p14ARF, and CDKN2B genes.42 Five tumors of our meningioma series without demonstrated homozygous deletion or mutation of CDKN2A, p14ARF, and/or CDKN2B lacked detectable transcripts for at least one of the p16INK4a, p14ARF, or p15INK4b proteins. However, only one of these tumors showed 5'-CpG hypermethylation of CDKN2A, p14ARF, and CDKN2B. Tse and colleagues37 investigated 23 meningiomas for methylation of CDKN2A and found partial rather than complete methylation in five tumors. The methylation status was not consistently associated with the expression of p16INK4a. Thus, it seems that the regulation of CDKN2A and CDKN2B transcription in meningioma cells is complex and may be influenced by yet unknown mechanisms in addition to hypermethylation.
In addition to the CDKN2 genes, other cell cycle-regulatory genes, such as CDK4, CDK6, RB1, and the cyclin D genes (CCND1, CCND2, and CCND3), are frequently aberrant in malignant tumors. We identified only one atypical meningioma with co-amplification of CDK4 and MDM2 among a total of 74 meningiomas investigated (present study and Weber and colleagues8 ). Two other studies did not detect any CDK4 amplification in meningiomas.36,37 Thus, amplification of CDK4 and/or MDM2 is rare in meningiomas. Amplification of CDK6 or any of the cyclin D genes has not been systematically investigated in meningiomas. Nevertheless, CGH studies did not reveal any amplification involving sequences from 7p13 (CDK6), 11q13 (CCND1), 12p13 (CCND2), or 6p21 (CCND3),8,43 suggesting that amplification of these genes is infrequent in meningiomas. The possibility of RB1 gene aberrations in those anaplastic meningiomas that have no detectable CDKN2A or CDKN2B alterations remains to be investigated. An immunohistochemical analysis of 23 meningiomas showed no aberrant pRB1 expression.37 The significance of this finding, however, is limited because no molecular genetic analyses were performed and most tumors were benign meningiomas.
In line with previous studies,44,45 we found no mutations in exons 5 to 8 of the TP53 gene in our meningioma series. A single anaplastic meningioma with a TP53 missense mutation was reported by Wang and colleagues.46 Although TP53 mutations are apparently rare in meningiomas, nuclear immunoreactivity for p53 protein has been detected in variable fractions of meningiomas.45,46
In summary, we performed a detailed analysis of human meningiomas for alterations of the tumor suppressor genes CDKN2A, p14ARF, CDKN2B, and CDKN2C. We found CDKN2C on 1p32 rarely altered in meningiomas and can, therefore, exclude this gene as the major target of the frequent losses on 1p in atypical and anaplastic meningiomas. Most anaplastic meningiomas either show homozygous CDKN2A, p14ARF, and CDKN2B deletions, CDKN2A and p14ARF mutations, or lack detectable expression of transcripts from one or more of these genes. Thus, inactivation of the G1/S-phase cell-cycle checkpoint is an important feature of anaplastic meningiomas that likely contributes to the rapid growth and malignant behavior of these tumors.
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Footnotes |
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Supported by grants from the Deutsche Krebshilfe/Dr. Mildred Scheel Stiftung (10-1361-Re2, 10-1639-Re3), the Wilhelm Sander Stiftung (2000.039.01), and the BONFOR program at the University of Bonn Medical Faculty (154/30).
J. B., B. M.-P., and M. W. contributed equally to this work.
Accepted for publication April 27, 2001.
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