Incidence of Numerical Chromosome Aberrations in
Meningioma Tumors as Revealed by Fluorescence In Situ
Hybridization Using 10 Chromosome-Specific Probes
Jose ´ Marı ´a Sayague ´s,1Marı ´a Dolores Tabernero,2Angel Maillo,3Pedro Dı ´az,3Ana Rasillo,1
Aglae Bortoluci,1Juan Gomez-Moreta,3Angel Santos-Briz,4
Francisco Morales,3and Alberto Orfao1*
1Servicio General de Citometrı ´a, Departmento de Medicina y Centro de Investigaciones del Ca ´ncer,
Universidad de Salamanca, Salamanca, Spain
2Hospital Universitario de Salamanca, Unidad de Investigacio ´n, Salamanca, Spain
3Neurosurgery Service, Hospital Universitario de Salamanca, Salamanca, Spain
4Departament of Pathology, Hospital Universitario de Salamanca, Salamanca, Spain
Objective: Although information on the cytogenetic characteristics of meningioma tumors has accumulated
progressively over the past few decades, information on the genetic heterogeneity of meningiomas is still scanty.
The aim of the present study was to analyze by interphase fluorescence in situ hybridization (FISH) the incidence
of numerical abnormalities for chromosomes 1, 9, 10, 11, 14, 15, 17, 22, X, and Y in a group of 70 consecutive
meningioma tumors. Another goal was to establish the potential associations among the altered chromosomes,
as a way to assess both intertumoral and intratumoral heterogeneity. Methods: For the purpose of the study, 70
patients diagnosed with meningioma were analyzed. Interphase FISH for the detection of numerical abnormalities
for chromosomes 1, 9, 10, 11, 14, 15, 17, 22, X, and Y was applied to fresh tumor samples from each of the
patients studied. Results: The overall incidence of numerical abnormalities was 76%. Chromosome Y in males
and chromosome 22 in the whole series were the most common abnormalities (46% and 61%, respectively).
Despite the finding that monosomy of chromosome 22/22q-deletions are the most frequent individual abnormality
(53%), we have observed that chromosome gains are significantly more common than chromosome losses (60%
versus 40%). Chromosome gains corresponded to abnormalities of chromosomes 1 (27%), 9 (25%), 10 (23%),
11 (22%), 14 (33%), 15 (22%), 17 (23%), and X in females (35%) and males (23%) whereas chromosome
losses apart from chromosome 22 frequently involved chromosomes 14 (19%), X in males (23%), and Y in males
on the other side, different association patterns were observed. Furthermore, in the latter group, monosomy
22/22q-was associated with monosomy X in females and monosomy 14/14q-was associated with nulisomy Y in
males. In addition, chromosome losses usually involved a large proportion of the tumor cells whereas chromo-
some gains were restricted to small tumor cell clones, including tetraploid cells. Conclusions: Our results show
that meningiomas are genetically heterogeneous tumors that display different patterns of numerical chromosome
changes, as assessed by interphase FISH. Cytometry (Clin. Cytometry) 50:153–159, 2002.
© 2002 Wiley-Liss, Inc.
Key terms: meningioma; chromosome aberrations; interphase cytogenetics; FISH
Over the last few decades, an increasing amount of
information has accumulated on genetic abnormalities in
meningioma patients (1–13). Most of this information has
been obtained through conventional cytogenetic studies
(3–6,10–12). Fluorescence in situ hybridization (FISH)
analysis of interphase nuclei was introduced during the
last decade for the study of numerical chromosomal ab-
normalities in meningioma tumors (7,8,14–18). From the
reported individual abnormalities, the monosomy 22/22q-
deletion is, by far, the most frequent aberration detected
in typical meningiomas (2,7,12,14,17,19–21). Other chro-
mosome abnormalities described as relatively frequent in
these tumors include loss/deletion of chromosomes 1p,
14q, 10q, and the sexual chromosomes (22–27). In con-
trast, chromosome gains and complex karyotypes are usu-
Grant sponsor: Consejerı ´a de Educacio ´n y Cultura of the Junta de
Castilla y Leo ´n, Valladolid, Spain; Grant number: 26/99; Grant sponsor:
Fondo de Investigaciones Sanitarias from the Ministerio de Sanidad y
Consumo (Madrid, Spain); Grant number: 01/1564.
*Correspondence to: Dr. Alberto Orfao, Servicio de Citometrı ´a, Hospi-
tal Universitario de Salamanca, Paseo de San Vicente, 58-182 37007
Received 5 November 2001; Accepted 18 January 2002
Published online in Wiley InterScience (www.interscience.wiley.com).
Cytometry (Clinical Cytometry) 50:153–159 (2002)
© 2002 Wiley-Liss, Inc.
ally found in a low proportion of cases. These findings
indicate that, as in other human tumors, meningiomas
represent a cytogenetically heterogeneous group of neo-
plasias. However, a careful analysis of the literature shows
the existence of disturbing levels of variability as regards
the exact incidence of specific genetic abnormalities in
meningiomas. As an example, the incidence of monosomy
22/22q-and monosomy 14/14q-ranges between 31% and
78% (14,28–31) and between 12% and 27% (23,26) of the
cases depending on the series analyzed. Although such a
variability could be related partially to the small number of
cases analyzed in many studies, it might also be due to the
use of different methods for the detection of specific
genetic abnormalities. Accordingly, conventional cytoge-
netics, which have been used in most studies, have been
shown to have several limitations related to the fact that
tumoral metaphases (32) are required. These include the
potential existence of clonal selection during cell culture,
the analysis of a small fraction (typically ?1%) of all the
cells present in the tumor sample, and the difficulties in
obtaining tumor cell metaphases in a significant propor-
tion of cases. In turn, in intephase FISH studies, either the
number of probes or the number of cases studied was
low. In addition, in these latter reports, single-probe stain-
ings and paraffin-embedded tissue samples have been
used frequently, which limit the possibilities of identifying
small populations of tumor cells (8).
The aim of the present study was to use interphase FISH
to analyze the incidence of numerical abnormalities for
chromosomes 1, 9, 10, 11, 14, 15, 17, 22, X, and Y in a
group of 70 consecutive meningioma tumors. Another
goal was to establish the potential associations among the
altered chromosomes, as a way to assess both intertu-
moral and intratumoral heterogeneity.
MATERIALS AND METHODS
Seventy consecutive patients diagnosed with meningi-
oma between 1990 and 1999 at the Neurosurgical Service
of the University Hospital of Salamanca were analyzed. Of
the patient sample, 31% were males and 69% females with
a mean age of 56 ? 15 years (range 16–81 years). All cases
were diagnosed with either intracranial (n ? 65) or spinal
(n ? 5) meningiomas after surgery. Tumor localization
was distributed as follows: cranial base including posterior
fossa, 39% of the cases; cerebral convexity, 24%; parasag-
ittal and tentorial, 26%; ventricular, 4%; and spinal cord,
7%. Diagnosis of meningioma was established in all cases
according to conventional histological criteria (33–35).
According to the World Health Organization (WHO) clas-
sification (36), 85% of the tumors were classified as grade
1 (including all benign subtypes), 6% as grade 2 (or atyp-
ical), and 9% as grade 3 (or anaplastic) meningiomas.
Interphase FISH was performed on fresh tumor samples
obtained from all patients at diagnostic surgery for the
detection of numerical abnormalities for chromosomes 1,
9, 10, 11, 14, 15, 17, 22, X, and Y. Samples corresponding
to a macroscopically tumoral region were cut, placed in
saline solution, and sent to the FISH laboratory for further
analysis of numerical chromosome abnormalities. Imme-
diately upon receipt, single-cell suspensions were ob-
tained from the samples using a well-established auto-
mated mechanical disaggregation procedure (37,38). Cells
were then resuspended in a 3/1 methanol/acetic (vol/vol)
and stored at -20°C until analysis. The following probes
were used in double stainings: chromosomes 9 and 22: LSI
bcr/abl dual-color probe, (Vysis, Downers Grove, IL) in-
cluding an abl probe conjugated with Spectrum Orange
(SO), which hybridizes to chromosome 9q34 and a bcr
probe conjugated with Spectrum Green (SG), which hy-
bridizes to chromosome 22q11.2; chromosomes 15 and
17: LSI PML/RAR-? dual-color probe (Vysis) containing a
PML probe conjugated with SO, which hybridizes to chro-
mosome 15q22, and a RAR-? probe conjugated with SG,
which hybridizes to chromosome 17q21; chromosomes
11 and 14: LSI IgH/CCD1 dual- color probe (Vysis), includ-
ing an IgH probe conjugated with SG, which hybridizes to
chromosome 14q32.3, and a CCND1 probe conjugated
with SO, which hybridizes to chromosome 11q13; chro-
mosomes X and Y: CEP X DNA probe (Vysis) conjugated
with SO, which hybridizes to the centromeric region of
chromosome X (Xp 11.1-q11.1), and CEP Y DNA probe
(Vysis) conjugated with SG, which hybridizes to the Yq12
region; chromosomes 1 and 10: CEP 1 DNA probe (Vysis)
conjugated with SO, which hybridizes to region 1q12, and
SG CEP 10 DNA probe (Vysis) conjugated with SG, which
hybridizes to region 10p11.1-q11.1. Fixed cells were
dropped on slides cleaned with ethanol/ether (1/1, vol/
vol) according to conventional cytogenetic protocols. The
slides were then incubated sequentially with a solution
containing 0.1 mg/ml pepsin (10 min at 37°C), fixed in 1%
acid-free formaldehyde (10 min at room temperature), and
dehydrated in decreased concentrations of ethanol in wa-
ter (100%, 95%, 70%) according to previously reported
techniques (39). The slides containing DNA from both
cells and probes were denatured at 75°C (1 min) and
immediately hybridized overnight (37°C) in a Hybrite ther-
mocycler (Vysis). Once this incubation period was com-
pleted, slides were washed sequentially for 5 min at 46°C
in 50% formamide/2 ? sodium chloride-sodium citrate
buffer (SSC) and in phosphate-buffered saline (PBS) with
1% Tween-20 (vol/vol). Cells were then counterstained
with 35 ?l of a mounting medium containing 75 ng/ml of
DAPI (Sigma, St. Louis, MO) and 5 ?l of Vectashield
(Vector Laboratories, Burlingame, CA) was used as the
The number of hybridization spots was evaluated using
a BX60 fluorescence microscope (Olympus, Hamburg,
Germany) equipped with a 100? oil objective. For each
slide, the number of hybridization spots per nuclei was
counted in at least 200 nuclei. For all slides measured, the
number of unhybridized cells in the areas assessed was
?1% and only spots with a similar size, intensity, and
shape were counted. The criteria used to define the pres-
ence of numerical abnormalities for each of the chromo-
somes analyzed were based on the study of 10 age and
SAYAGUE´S ET AL.
sex-matched normal control bone marrow samples. The
mean percentage (?SD) of nuclei with a higher/lower
number of spots than expected in these control samples
for the chromosomes assessed was as follows: chromo-
some 1, 0.1 ? 0.3%/2.1 ? 1.6%; chromosome 9, 0.3 ?
0.9%/5.5 ? 2.6%; chromosome 10, 0.1 ? 0.2%/0.9 ?
0.6%; chromosome 11, 0.2 ? 0.2%/0.8 ? 0.6%; chromo-
some 14, 2.0 ? 3.16%/2.88 ? 3.44%; chromosome 15,
0.8 ? 0.7%/1.2 ? 0.8%; chromosome 17, 0.5 ? 0.8%/
5.6 ? 2.8%; chromosome 22, 2.91 ? 3.65%/1.0 ? 1.59%;
chromosome X females, 2.0 ? 1.4%/0.0 ? 0.0%; chromo-
some X males, 0.1 ? 0.3/0.7 ? 2.1%; and chromosome Y
males, 0.8 ? 1.0%/1.4 ? 1.7%. A patient was considered
to carry a numerical chromosomal abnormality when the
proportion of cells displaying a proportion of events with
an abnormal number of spots was at percentages higher
than the mean value plus 2 SD of the percentages obtained
for that specific chromosome in normal controls.
The frequency of cells per tumor sample and of cases
carrying specific chromosomal abnormalities was calcu-
lated using SPSS (version 8) software (SPSS, Chicago, IL).
A multivariate stepwise regression analysis (regression,
SPSS) was performed to examine the correlation between
the numerical abnormalities found for each chromosome
and both the aberrations detected for the other chromo-
somes analyzed and the overall percentage of tumor cells
present in the sample that carried numerical abnormalities
for at least one of the studied chromosomes. Statistical
significance was considered to be present when P ? 0.05
Of the 70 meningioma patients included in the present
study, 53 (76%) displayed numerical abnormalities for at
least 1 of the 10 chromosomes analyzed. Overall, chromo-
some gains were observed more frequently than chromo-
some losses, i.e., 60% versus 40% of all numerical chro-
mosome abnormalities detected (Fig. 1). However, once
individual chromosomes were considered, chromosome
22 in the whole series and chromosome Y in males were
the most frequently altered (43 of 70 [61%] and 10 of 22
[45%], respectively). Their abnormalities mainly corre-
sponded to monosomy 22/22q-deletions (37 of 43 [86%])
and nulisomy Y (7 of 10 [70%]). Other chromosomes that
were altered frequently in number were chromosomes 14
(33%) and X in females (35%), loss of either of the two
chromosomes being more frequent than their gains: 19%
versus 14% and 23% versus 12%, respectively. The remain-
ing chromosomes analyzed were aberrant at lower fre-
quencies: chromosome 1 in 27% of cases, chromosome 9
in 25%, chromosome 10 in 23%, chromosome 11 in 22%,
chromosome 15 in 22%, chromosome 17 in 23%, and
chromosome X in 23% of males. Interestingly, the majority
of the abnormalities for this group of chromosomes cor-
responded to chromosome gains: chromosome 1, 26%;
chromosome 9, 22%; chromosome 10, 17%; chromosome
11, 22%; chromosome 15, 22%; chromosome 17, 22%; and
chromosome X in males, 23%. Table 1 shows the specific
abnormalities detected for each chromosome. Chromo-
some losses constantly corresponded to either mono-
somies almost exclusively restricted to chromosomes 22,
14, X in females or to nulisomy Y in males. In contrast,
chromosome gains included trisomies and/or tetrasomies
together with disomy Y. In addition, our results show that
regarding chromosome gains, trisomies alone and in com-
FIG. 1. Incidence of numerical abnormalities for chromosomes 1, 9,
10, 11, 14, 15, 17, 22, X, and Y by FISH in 70 meningioma patients.
Results are expressed as percentage of cases. Xf, chromosome X in
females; Xm, chromosome X in males. Filled bars, chromosome losses;
open bars, chromosome gains.
Incidence of Numerical Abnormalities for Chromosomes 1, 9, 10, 11, 14, 15, 17, 22, X, and Y
in 70 Meningioma Patients (n ? 70)*
*Results expressed as percentage of cases. Xf, chromosome X in females; Xm, chromosome X in males.
CHROMOSOME ABERRATIONS IN MENINGIOMA BY FISH
bination with tetrasomies were relatively infrequent and
were present in ?7% of the cases analyzed here for each
chromosome. In contrast, disomy Y and tetrasomies were
detected more frequently, their incidence being similar
for chromosomes 1 (13%), 9 (13%), 10 (13%), 11 (17%), 14
(10%), 15 (13%), 17 (11%), and Y (14%). Both tetrasomy
22 and tetrasomy X in females were found at significantly
lower frequencies (3% and 6% of the cases, respectively).
Upon analyzing the potential existence of an association
between the different numerical abnormalities detected,
we observed a statistically significant association among
gains of chromosomes 1, 17, 11, and 15 (Table 2). Chro-
mosomes 17, 11, and 15 were also associated with gains of
chromosome X in males whereas the numerical abnormal-
ities of chromosomes 1 and 17 were related to trisomy
and/or tetrasomy 9. Similarly, a significant association was
also found among the numerical abnormalities of chromo-
somes 10, 14, and X in females, the loss of the latter two
chromosomes being associated significantly with abnor-
malities of chromosome Y (P ? 0.001) and monosomy 22
(P ? 0.004), respectively.
A significant correlation was observed between the
percentage of cytogenetically abnormal tumor cells and
the proportion of cells carrying numerical abnormalities
for each of the chromosomes analyzed except chromo-
somes X and Y in males (Table 3). Nevertheless, this
correlation was poor (r ? 0.49) for all studied chromo-
somes except 22 (r ? 0.84) and X (r ? 0.68) in females
Based on the analysis of 70 meningioma tumors, we
showed that numerical abnormalities for one or more
chromosomes occurred frequently (76%) in meningiomas,
as reported in previous studies (9,17,23). However, com-
pared with many previous reports, we obtained results in
all of the cases analyzed and for each sample information
was available for almost every cell nuclei.
Our results show that the overall incidence of chromo-
some gains is higher than that of chromosome losses.
However, it should be noted that the proportion of cells
per sample carrying chromosome losses was far higher
than that of cells displaying chromosome gains (mean of
65 ? 32% and 15 ? 26%, respectively). As reported
previously, monosomy 22/22q-deletions were the most
frequent individual abnormality detected in more than
one half of the patients.
Additional chromosome losses frequently involved
chromosome X in females and Y in males, as well as
chromosomes 14 and, to a lesser extent, 10. Loss of a sex
Correlation Between the Numerical Abnormalities Observed for Chromosomes 1, 9, 10, 11, 14, 15, 17, 22, X, and Y*
19 1011 14151722Xf Xm
R ? 0.644
P ? 0.005
R ? 0.775
P ? 0.003
11 NS NS
R ? 0.754
P ? 0.002NS
R ? 0.639
P ? 0.019
R ? 0.843
P ? 0.000
R ? 0.866
P ? 0.000
R ? 0.780
P ? 0.002
R ? 0.675
P ? 0.011
R ? 0.924
P ? 0.000
Xf NS NS
R ? 0.668
P ? 0.049NS
R ? 0.765
P ? 0.010NSNS
R ? 0.690
P ? 0.004
Xm NSNS NS
R ? 0.655
P ? 0.021 NS
R ? 0.635
P ? 0.020
R ? 0.546
P ? 0.043NSNS
R ? 0.821
P ? 0.000 NSNS NS NSNS
*NS, no statistically significant (P ? 0.05) association was found. R, coefficient of correlation; Xm, chromosome X in males; Xf,
chromosome X in females.
Correlation Between the Overall Percentage of Cytogenetically
Abnormal Tumor Cells and the Number of Cells Carrying
Numerical Abnormalities for Chromosomes
1, 9, 10, 11, 14, 15, 17, 22, X, and Y*
*Xm, chromosome X in males; Xf, chromosome X in females.
SAYAGUE´S ET AL.
chromosome in somatic cells is a relatively frequent age-
related phenomenon, usually including loss of the Y chro-
mosome in bone marrow cells from older male individuals
(40). However, it was never found at the high frequencies
reported here. Interestingly, loss of chromosome X in
females was associated with abnormalities of chromo-
some 22 whereas loss of chromosome Y in males showed
an association with monosomy 14/14q-as detected by the
LSI IgH probe directed against 14q32. To the best of our
knowledge, this is the first time that such an association is
reported. These findings would support the existence of
unique patterns of chromosome losses in male compared
with female meningioma patients, in whom the sex chro-
mosomes would also be involved. Further studies are
necessary to confirm our observations and explore their
potential clinical implications.
Regarding chromosome gains, it should be noted that
they usually consisted of tetrasomies either alone or in the
presence of trisomic clones, isolated trisomies being in-
frequent. These findings, together with the similar inci-
dence of chromosome gains found for the 1, 9,10, 11, 14,
15, 17, and Y chromosomes, support the notion that
during aneuploidization, meningioma tumors frequently
go through a tetraploid stage. This hypothesis is sup-
ported further by the fact that statistically significant as-
sociations were found among gains of chromosomes 1, 9,
11, 15, 17, and X in males and by the observation of
tetraploid cells in many FISH double stainings (Fig. 3).
Furthermore, a relatively poor degree of correlation was
found between the percentage of cells carrying gains for
each of the chromosomes listed above and the overall
number of cytogenetically abnormal tumor cells, further
supporting intratumoral occurrence of chromosome
gains/tetraploidization in meningiomas at a relatively late
stage of the aneuploidization process. The frequent pres-
ence of only two copies for chromosomes 22 and X in
females in the tetraploid cells (Fig. 3) supports the estab-
lished hypothesis that loss of these chromosomes occurs
at an earlier stage compared with tetraploidization (18).
The relatively high incidence of tetraploid clones found
in the present study contrasts with findings reported in
the literature. Actually, with the exception of the study
reported by Muller et al. (18), who found tetraploid cells
by FISH as a result of endoduplication of the tumor cells,
this phenomenon has not been described in the literature.
Such an apparent discrepancy could be explained, at least
to a certain extent, by the fact that tetraploid cells usually
represent a minor fraction of the total tumor cells and
therefore they could be missed if only a small number of
cells/metaphases are analyzed. Alternatively, tetraploid tu-
mor cells could undergo a negative clonal selection during
Monosomy 14/14q-, as detected by the LSI IgH probe
directed against the IgH gene located at chromosome
14q32, was found in around 20% of all meningioma tu-
mors. It has been suggested that 14q24.3-q32.33 may also
represent a critical chromosome region that is lost not
only in meningioma tumors (3,41), but also in Ewing’s
sarcoma (42) and in leiomyosarcoma (43). In this sense,
specific deletions of 14q22-24 and 14q32, where the AKT
(44), ELK-2 (45; a member of the ETS family of onco-
genes), and TC1-1 (46; another oncogene) genes are lo-
cated, appear to be of particular relevance. In spite of this,
monosomy 14/14q-abnormalities were also associated
with other chromosome losses, supporting the notion that
tumor progression is associated with loss of different chro-
mosome regions. Monosomy 14/14q-deletions were asso-
ciated with loss of chromosome Y in males, but not
FIG. 2. Correlation between the percentage of cytogenetically abnormal meningioma tumor cells present in tumor samples and the proportion of cells
carrying numerical abnormalities for chromosomes 22 and X in females.
CHROMOSOME ABERRATIONS IN MENINGIOMA BY FISH
monosomy 22/22q-as detected by hybridization for the
bcr gene or monosomy X in females.
Interestingly, monosomy 1 was an infrequent finding
(1%) in our study, in contrast to that reported by other
groups using FISH analysis. In other studies, probes for
chromosome 1p were used whereas we assessed numer-
ical abnormalities of chromosome 1 with a probe directed
against the pericentromeric heterochromatin of chromo-
some 1q. This observation would further support the
hypothesis that 1p deletions involving 1p36, 1p35-p32,
and/or 1p22-p13, but not monosomy 1, play an important
role in tumorigenesis of meningiomas due to the presence
at these regions of tumor suppressor genes such as the
RAD54 (47,48), P73 (49), and APLP (18). In addition, our
results would also help to explain why gains of chromo-
some 1 found in more than 10% of the cases might even-
tually correspond to trisomy 1q, reported by others who
used conventional cytogenetic techniques (23) based on
the fact that the probe used detects the pericentromeric
heterochromatin of chromosome 1q12.
In summary, our results show that genetically, menin-
giomas are highly heterogeneous tumors, numerical chro-
mosome abnormalities being found in most cases once
interphase FISH is used. Regarding individual chromo-
somes, entire or partial loss of chromosome 22, as de-
tected by a probe directed to the bcr gene, was the most
frequent individual abnormality. Once present, this abnor-
mality involves almost all tumor cells. In contrast, chro-
mosome gains are restricted frequently to a minor clone
and are consistent with the occurrence of tetraploidiza-
tion at a latter stage of the tumorigenesis process. Al-
though an association was found among most gained chro-
mosomes on one side and chromosome losses on the
other side, different association patterns were observed.
The most intriguing were those of monosomy 22/22q-,
with monosomy X in females and monosomy 14/14q-with
nulisomy Y in males.
J.M.S. is recipient of a grant from the Consejerı ´a de
Educacio ´n y Cultura of the Junta de Castilla-Leo ´n, Vallado-
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CHROMOSOME ABERRATIONS IN MENINGIOMA BY FISH