REVIEW
Chromosomal abnormalities subdivide neuroepithelial tumors
into clinically relevant groups
Yuichi Hirose and Kazunari Yoshida
Division of Neurosurgery, Department of Surgery, Keio University School of Medicine, Tokyo, Japan(Received for publication on November 22, 2005)(Revised for publication on March 9, 2006)(Accepted for publication on March 16, 2006)

Abstract. Gliomas are the most common primary brain tumor, and are histopathologically classiﬁed
according to their cell type and the degree of malignancy. However, sometimes diagnosis can be controversial, and tumors of the same entity possibly have a wide range of survival. Genetic analysis ofthese tumors is considered to have great importance in terms that it can provide clinically relevant
classiﬁcation of the tumors and compensate for the limitation of the histological classiﬁcation. Previous
studies using comparative genomic hybridization (CGH) demonstrated that copy number aberrations(CNAs) were frequently recognized in these tumors, and revealed that a gain on chromosomal arm 7q
was the most common CNA in diffuse astrocytomas, whereas a small population of the tumor showed
losses on 1p/19q which characterizes oligodendrogliomas with good responsiveness to chemotherapeutic regime using procarbazine, nitrosourea and vincristine. High grade (malignant) gliomas(i.e. anaplastic astrocytomas, anaplastic oligodendrogliomas and glioblastomas) have been reported tohave a gain on 7p and losses on 9p and 10q. In case of ependymomas, frequent chromosomal aberrations in intracranial tumors were a gain on 1q and losses on 6q, and, on the other hand, a gain on
chromosome 7 was recognized almost exclusively in spinal cord tumors. These data suggest that intracranial and spinal cord ependymomas are different genetic diseases and comprise different subgroups
within one histological entity. In conclusion, genetic analysis of gliomas may help to classify thesetumors and provide leads concerning their initiation and progression. The relationship of these aberrations to patient outcome needs to be addressed. (Keio J Med 55 (2): 52–58, June 2006)
Key words: comparative genomic hybridization, astrocytoma, oligodendroglioma, ependymoma

to date. However, there are limitations in the systems
presently used to deﬁne these tumors since interpreting cellularity, anaplasia, or even cell type is notalways easy because of the histological heterogeneity
when the tumor is of histologically high grade or mixed
type (i.e. oligo-astrocytoma) and the lack of any tumorspeciﬁc marker when the tumor’s histologic grade islow. Thus, there are wide variations in the frequency ofthe diagnoses ‘‘oligodendroglioma’’ and ‘‘astrocytoma’’,and even practicing neuropathologists who examine
cases together regularly with the object of producing
consensus diagnosis sometimes fail to reach agreement.4–6 Distinct diagnostic criteria therefore may help
to explain why the clinical outcome varies widely within
the same histologic grade, for example, median survival

Introduction
Gliomas, tumors of neuroepithelial cell origin, comprise the most frequent primary brain neoplasm. Thesetumors are classiﬁed according to their histopathological ﬁnding based on determination of the cellular
type (i.e. astrocytomas, oligodendrogliomas and ependymomas are considered to consist of astrocytic, oligodendroglial and ependymal cells, respectively).1 Furthermore, histological grades are deﬁned by themalignant features of the tumor, and, in general, tumor
response to therapy varies with histological grade.2,3Histological evaluation has been the most importantdiagnostic examination in making a decision on themost appropriate treatment strategy for glioma patients

Reprint requests to: Dr. Kazunari Yoshida, Division of Neurosurgery, Department of Surgery, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan, e-mail: kazrmky@sc.itc.keio.ac.jp52Keio J Med 2006; 55 (2): 52–58

for diffuse astrocytoma is 5–7 years but some patients
progress quickly to a higher grade.7–9
Chromosome aberrations, mutations, and ampliﬁcations occur frequently in gliomas. Malignant progression has been associated both with particular genetic
abnormalities and an increase in the number of aberrations.10,11 The molecular events that trigger the development of low grade gliomas are unknown. However,
it is believed that alterations of particular genes are
responsible for the way a tumor behaves. A better
understanding of glioma initiation may help to identify
groups at risk for early progression, and speciﬁc genetic
aberrations may serve as reliable predictors of clinicaloutcome. For example, Cairncross et al. reported thatallelic loss (or loss of heterozygosity) of chromosome 1p was a statistically signiﬁcant predictor ofchemosensitivity for anaplastic (malignant) oligodendrogliomas, and that combined loss involving chromosomes 1p and 19q was statistically signiﬁcantly
associated with both chemosensitivity and longer
recurrence-free survival after chemotherapy although
no clinical or pathologic feature of these tumors had
previously allowed accurate prediction of their response to chemotherapy.12 Thus, the importance ofgenetic analysis on gliomas has been widely acknowledged recently, whereas the histological examination
still provides information indispensable to treatment ofgliomas. In this article, the authors review reports on
genetic analysis of gliomas and clues to establish clinically relevant diagnostic criteria in combination withhistological subtyping of these tumors.
Comparative Genomic Hybridization (CGH)
Comparative genomic hybridization (CGH) is a genetic analytical method to determine gains and losses ofgenetic material in tumors and cell lines.13–15 CGH
detects and maps copy number aberrations (CNAs) as afunction of the position on normal chromosomes. Tumor and normal DNAs are labeled with different ﬂuorophores, usually green and red, and simultaneously
hybridized to normal metaphase chromosomes (Fig. 1).
If DNA is ampliﬁed in the green-labeled tumor DNA,
more green-label than red-label will hybridize to homologous sites in the normal metaphase. If DNA is deleted
in tumor DNA, less green signal will hybridize. Thus,
the ratio of ﬂuorescence intensities along the normal
metaphase chromosomes measures and maps alterations in the DNA sequence copy number throughout
the genome. In case of inﬁltrating tumors such as diffuse astrocytomas, such investigations can be difﬁcult,since samples are often intermixed with normal brain
because of the tumor’s inﬁltrative nature.16 Therefore,
methods to exclude normal tissue and utilize small
amounts of DNA for CGH are needed. A previous

53

Fig. 1 Schematic illustration of comparative genomic hybridization(CGH). Test (tumor) DNA and reference (normal) DNA (obtained
from lymphocytes of healthy donors) are labeled with different ﬂuorophores, usually test DNA in green and reference DNA in red.
These labeled DNAs are co-hybridized to target metaphase chromosomes which are prepared from normal lymphocytes and spread on aslide glass. Hybridization is captured under the ﬂorescence microscope and the ratio of the intensity of the green to the red ﬂuorescence is analyzed along the axis of each chromosome with computer
software. The ratio is higher than 1.0 in the region where the tumor
has an increased number of DNA copies, and lower than 1.0 in theregion where the tumor has a decreased number of DNA copies
compared with normal DNA.

study validated a CGH method that uses DNA prepared from microdissected ﬁxed tissues using a degenerate oligonucleotide-primed polymerase chain reaction (DOP-PCR).17 This technique uses speciﬁc PCRprimers to make a global representation of small
amounts of DNA.18–20 Consecutive sections from aformalin ﬁxed parafﬁn embedded block are cut andmounted. One slide is stained with hematoxylin andeosin (HE) and the rest with methyl green (MG). Afterthe HE slide is marked to deﬁne areas for microdissection, a small piece of tissue (<5  5 mm) from theMG slide within the area corresponding to the marked
area on the HE slide is microdissected. DNA isextracted from these pieces and subjected to DOPPCR. Labeling of test (tumor) DNA and reference(normal) DNA are accomplished with another DOPPCR reaction. Metaphase spreads are prepared fromphytohemaglutinin-stimulated human peripheral blood
lymphocytes from a normal healthy male. The probes

54

Hirose Y and Yoshida K: Chromosomal aberrations in gliomas

are hybridized to metaphase spreads, and, after washing away unhybridized probes, the metaphase spread isobserved under ﬂuorescence microscope and images
are acquired with an image processing system. The
ratios of ﬂuorescence intensity along the chromosomes
are quantiﬁed.
Diffuse Astrocytomas (low grade astrocytomas)
Hirose et al. studied 30 cases of diffuse astrocytoma
using tissue microdissection and DOP-PCR as described above.21 CNAs were recognized in more than
80% of the cases analyzed. The most frequent aberration was a gain on chromosome arm 7q. The ﬁnding
agreed with the results published by Schröck et al, who
saw similar gains in ﬁve of 10 grade II cases.15 A previously reported limited karyotypic analysis of a small
number of grade II cases suggested the involvement ofchromosome 7.22,23 Furthermore, rat astrocytomas
induced by ethylnitrosourea frequently had a gain on
rat chromosome 4, which shares considerable homology
with human chromosome 7.24 Since the involvement ofchromosome 7 in low grade tumors agreed with theresults showing that a gain on chromosome 7 was themost frequent aberration in malignant (high grade)
astrocytomas as mentioned in the next section,25–29 thisgain on 7q appeared to be a key early event in a subgroup of astrocytomas (Fig. 2), and appeared to be
most frequent in tumors arising in adults.16,27–29
Candidate oncogenes on 7q include MET, a gene at
7q31 which encodes the receptor for hepatocyte growth
factor/scatter factor,30,31 and its transcript is abundant in these tumors.32,33 However, MET is only one ofmany possible ampliﬁed sequences on 7q. Since CGH
can detect highly ampliﬁed sequences >2–5 megabasesin length,34 a more sensitive assay system, for example
DNA microarray CGH35 or normalized expression
arrays targeted to chromosome 7 are possible methods
that may help to narrow the region of interest.
Malignant (high grade) Astrocytomas(anaplastic astrocytomas and glioblastomas)
Concerning high grade astrocytomas, anaplastic
astrocytomas and glioblastomas, several CGH studies
have been published.25–29 Mohapatra et al. reported
that there were fewer CNAs in anaplastic astrocytomas(median ¼ 4) than in glioblastomas (median ¼ 7), consistent with the idea that lower grade tumors are moregenetically stable with fewer genetic aberrations thanhigher grade tumors.26 These tumors differed in boththe quality and the quantity of their CNAs. Glioblastomas had more ampliﬁcations present than anaplastic astrocytomas, and the most frequent was at
7p12, the location of EGFR.

Fig. 2 Genetic model of progression of ‘‘astrocytic’’ and ‘‘oligodendroglial’’ tumors. Published data suggest that tumors with a gain on 7q
and losses on 1p/19q are of astrocytic and oligodendroglial lineage,
respectively, regardless of their morphological (histological) aspects.
Low grade (WHO grade 2) ‘‘astrocytic’’ tumors develop from normal
cells (or tumor precursor cells) with a gain on 7q, and as the tumor
grade progresses to grade 3, a gain on 7p and/or a loss on 9p areadded. Grade 4 tumors (glioblastomas) are characterized by a loss on
10q in addition to the CNAs described above. In case of ‘‘oligodendroglial’’ tumors, grade 2 tumors are characterized by losses on 1p
and 19q, and grade 3 tumors have additional aberrations of a gain on
7, a loss on 9p and/or a loss on 10q. Note that high grade (malignant,
WHO grade b 3) astrocytic and oligodendroglial tumors share thecommon genetic events even though a gain on 7q (most frequent inastrocytomas) and a loss on 1p/19q (most frequent in oligodendroglioma) were mutually exclusive aberrations when tumors were ata histologically low grade (WHO grade 2).

Kunwar et al. reported that most gains on chromosome 7 in glioblastomas involved the whole chromosome, whereas most gains on chromosome 7 in primary
anaplastic astrocytomas, as well as low grade astrocytomas, involved pieces of the chromosome.25 These
differences suggest that mechanisms of genetic damage
leading to CNAs on chromosome 7 differ in anaplastic
astrocytomas and glioblastomas, although they have thecommon effect of increasing the copy number on partsof chromosome 7 (Fig. 2). They also indicated that
CNAs involving chromosome 7 are key determinants ofclinical outcome, such as those with longer survival(normal 7) and those with extremely poor survival(þ7p), and concluded that a gain on 7p represented apoor prognostic marker. Patients with tumors that contained no aberrations had greater than 5 years followup, and this trend is similar to that observed for low
grade astrocytomas with no CNAs.21

Keio J Med 2006; 55 (2): 52–58

Burton et al. tried to identify CNAs likely related tothe clinical outcome of glioblastomas,36 and revealed
that tumors from long-term survivors (>3 years) exhibited fewer genetic aberrations, on average, than tumors
from short-time survivors. They concluded that aberrations previously implicated in the molecular pathogenesis of glioblastomas (gain on 7, loss on 9p, and losson 10q) were, in general, less frequent in long-timesurvivors and additional aberrations not previously
emphasized as potentially prognostic (6q loss and 19q
gain) were associated with the short-time survivor
group. Conversely, a loss on 19q was restricted to longtime surviving patients and was considered to represent
a marker of improved outcome in glioblastoma patients.
Oligodendrogliomas
Since Cairncross et al. reported that anaplastic oligodendrogliomas with losses of heterozygosity (LOH)on chromosomal arm 1p and 19q had shown remarkably good response to chemotherapy using procarbazine, nitrosourea and vincristine,12 various genetic
analyses on 1p/19q have been widely undertaken.5,37–41
In every method, DNA copy number losses on 1p and
19q were the most frequent aberration in oligodendroglial tumors. Bigner et al. reported that, although
LOH analysis was regarded as the gold standard for
detecting losses on 1p and 19q in oligodendroglial
tumors, CGH and LOH showed an excellent correlation between losses on these chromosomal arms
undoubtedly because the regions of loss were large.39
In studies using CGH, which offers the advantage in
LOH analysis of being able to conduct an investigationon the whole genome at a single analysis, low gradeoligodendrogliomas had losses on 1p and 19q, either
alone or with additional gains or losses (with no consistent pattern).5,39,40 Anaplastic (high grade) oligodendroglioma had many molecular features in common
with the well-differentiated oligodendrogliomas including losses on 1p and 19q, but also had additional deviations of a gain on chromosome 7 and losses on 4, 9p and10.39,40 A CGH study on recurrent anaplastic oligodendrogliomas also conﬁrmed that a gain on 7 and aloss on 10 could occur during malignant progression of
typical oligodendroglial tumors that contain losses
involving chromosomes 1p and 19q.40 It is noteworthy
that high grade (malignant) oligodendrogliomas sharethe common genetic events even though losses on 1p/
19q and a gain on 7q were mutually exclusive whentumors were at a histologically low grade. These datasuggest that oncogenesis of these tumors occurs in different genetic pathways, and that they progress throughthe common pathway consisting of a gain on 7 (7p) anda loss on 10 (Fig. 2). However, even when these aberrations are associated, losses on 1p/19q still characterize

55

oligodendrogliomas as having a good response to chemotherapy, which differentiates anaplastic oligodendrogliomas from high grade astrocytomas, especiallyglioblastomas, the most malignant astrocytomas. Several
studies have reported that expression of DNA repair
enzyme O 6 -methylguanine-DNA methyltransferase,
which renders the tumor resistant to DNA-alkylating
chemotherapeutic agents, was low in the tumors with
1p/19q losses.41–43 However, the mechanism of thesilencing of this enzyme in association with losses on
1p/19q is still unclear.
Ependymomas
A CGH study showed clear and more remarkable
cytogenetic differences between tumors that occurred in
intracranial and spinal cord ependymomas.44 First,
there were far more CNAs in spinal cord than in intracranial tumors. Secondly, the CNAs in these two groups
were different. Spinal cord tumors featured a gain on
chromosome 7. Other frequent CNAs seen in the spinal
cord cases included gains on 2, 5, 9, 12, 15, 18, 20q andX; and losses on 13q and 22q; these CNAs were far lessfrequent in the intracranial cases. On the other hand,cases of intracranial tumors, especially those of grade 3,
had frequent gains on 1q and losses on 9; these CNAs
were nearly absent in the spinal cord tumors. Carter
et al. conﬁrmed this ﬁnding by analyzing 86 ependymomas from children and adults.45 It is well known that
intracranial tumors frequently relapse46,47 and thatspinal cord tumors rarely relapse after gross total resection.48 These data suggest that intracranial and spinal
cord ependymomas progress along substantially different pathways although they comprise one histologic
entity. CNAs frequently seen in other intracranial neuroepithelial tumors, gain on 7, losses on 1p/19q, and aloss on 10q were rare in intracranial ependymomas,
which suggests that ependymomas develop throughunique genetic modiﬁcations compared with astrocytomas and oligodendrogliomas. The relationshipof intracranial ependymoma grade to outcome is controversial.49,50 Nonetheless, there were indications thata gain on 1q and a loss on 9 were preferentiallyassociated with histologic grade 3 among intracranialtumors, therefore these CNAs might be indicators ofoutcome. The data also suggested that intramedullaryspinal cord ependymomas and myxopapillary ependymomas were different genetic subgroups although bothshared the common genetic characteristic of chromosome 7 gain. Loss on 22q, gains on 15q and 12 did notoccur in myxopapillary tumors, while losses on chromosomes 1, 2, and 10 occurred solely in the myxopapillary group. Even though myxopapillary tumors
grow slowly,48 they do have a greater potential for dissemination through the central canal than other spinal

56
Table 1Hirose Y and Yoshida K: Chromosomal aberrations in gliomas
Comparison of Genetic Characteristics between Intracranial and Spinal Cord Ependymomas

Location
Histology
Frequent aberration

Intracranial
grade 2no consistent pattern

Range of aberration
Aberrations per case

Spinal cord
grade 3
þ1q, 6q, 9p

partial chromosome
few

ependymomas.51 Thus, different CNAs in these twogroups of spinal ependymomas may underlie differences in their clinical behavior.
In the case of ependymomas, CNAs are well correlated to the histology in the case of spinal cord ependymomas, but, intracranial and spinal (intramedullary)tumors, which are histologically classiﬁed into one entity as ‘‘ependymoma’’, were clearly differentiated bygenetic analysis. This is an example which supports theidea that genetic analysis can provide information on
oncogenesis of the tumors, which has not been achievedby histological examination.
Conclusion
Although genetic assay systems that are more sensitive than CGH, for example DNA microarray CGH,
have been developed recently, CGH has the advantage
of utilizing archival parafﬁn-embedded tissue, and canprovide genetic data which have profound implications
for understanding and predicting the behavior of neuroepithelial tumors. At present, the loss of 1p/19q alone
is the only genetic marker that helps in the decision regarding therapy for gliomas, and this fact limits theclinical usefulness of genetic analysis. However, theauthors believe that genetic proﬁles can supplement
current histological criteria to improve the accuracy ofsurvival predictions and eventually to provide a moreobjective method than histology for classifying tumors.
Information on chromosomal aberrations in gliomas
will provide a clue to develop a reliable and more simpliﬁed method to detect much smaller genetic abnormalities in the tumor. On the basis of the associations
between clinical and genetic characteristics, further investigation is needed to identify genes in the chromosomal regions implicated in tumor development andbehavior.
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