biology of central nervous system tumors
David N. Louis, M.D., MGH Division of Neuropathology
Webster K. Cavenee, Ph.D., University of California at
transformation appears to be a multi-step process in which
the normal controls of cell proliferation and cell-cell
interaction are lost, thus transforming a normal cell
into a tumor cell. This tumorigenic process involves an
interplay between at least two classes of genes: oncogenes
and tumor suppressor genes. Oncogenes are abnormally activated
versions of cellular genes that promote cell proliferation
and growth. Activated oncogenes thereby result in an exaggerated
impulse for a cell to grow and divide. Tumor suppressor
genes, on the other hand, are normal genes that act to
inhibit cell proliferation and growth. The inactivation
of these genes results in tumor formation or progression.
The most common scenario for inactivation of both copies
of a tumor suppressor gene is mutation of one allelic
copy, followed by loss of all or part of the chromosome
bearing the second allelle. Consequently, the identification
of consistent regions of chromosomal loss in specific
tumor types suggests a tumor suppressor gene in that chromosomal
region. These basic themes of oncogene activation and
tumor suppressor gene inactivation coupled with chromosomal
homozygosity, underlie the current molecular understanding
of human tumor formation. The following chapter reviews
the emerging knowledge on the molecular basis of brain
tumorigenesis, covering primary tumors of the brain as
well as other primary intracranial neoplasms that commonly
affect the central nervous system.
Diffuse, fibrillary astrocytomas
of low-grade astrocytoma
fibrillary astrocytomas are the most common type of primary
brain tumor in adults. These tumors are divided histopathologically
into three grades of malignancy: World Health Organization
(WHO) grade II astrocytoma, WHO grade III anaplastic astrocytoma
and WHO grade IV glioblastoma multiforme (GBM). WHO grade
II astocytomas are the most indolent of the diffuse astrocytoma
spectrum. Nonetheless, these low-grade tumors are infiltrative
and have a marked potential for malignant progression,
and any biological model for astrocytomas must account
for these cardinal features of malignant progression and
gene, a tumor suppressor gene located on chromosome 17p,
has an integral role in a number of cellular processes,
including cell cycle arrest, response to DNA damage, apoptosis,
angiogenesis and differentiation; as a result, p53 has
been dubbed the "guardian of the genome". The
p53 gene is involved in the early stages of astrocytoma
tumorigenesis 1. For instance, p53 mutations and allelic
loss of chromosome 17p are observed in approximately one-third
of all three grades of adult astrocytomas, suggesting
that inactivation of p53 is important in the formation
of the grade II tumors. Moreover, high grade astrocytomas
with homogeneous p53 mutations evolve clonally from subpopulations
of similarly mutated cells present in initially low grade
tumors 2 . Such mutation studies are complemented by functional
studies that have recapitulated the role of the p53 inactivation
in the early stages of astrocytoma formation. For instance,
cortical astrocytes from mice without functional p53 appear
immortalized when grown in vitro and rapidly acquire a
transformed phenotype. Cortical astrocytes from mice with
one functional copy of p53 behave more like wild-type
astrocytes and only show signs of immortalization and
transformation after they have lost the one functional
p53 copy 3,4. Interestingly, those cells without functional
p53 become markedly aneuploid 3, confirming prior work
showing that p53 loss results in genomic instability 5
and that astrocytomas with mutant p53 are often aneuploid
6. Thus, the abrogation of astrocytic p53 function appears
to facilitate some events integral to neoplastic transformation,
setting the stage for further malignant progression.
growth factors and their receptors are overexpressed in
astrocytomas, including platelet-derived growth factor
(PDGF), fibroblast growth factors (FGFs), and vascular
endothelial growth factor (VEGF). For example, PDGF ligands
and receptors are expressed approximately equally in all
grades of astrocytoma, suggesting that such overexpression
is also important in the initial stages of astrocytoma
formation. Tumors often overexpress cognate PDGF ligands
and receptors in an autocrine stimulatory fashion 7. The
mechanisms for PDGF overexpression in most cases have
not been elucidated, although rare astrocytomas display
amplification of the PDGF a-receptor gene. Significantly,
loss of chromosome 17p in the region of the p53 gene is
closely correlated with PDGF a-receptor overexpression,
in that 17p loss is most often seen in those astrocytomas
that have PDGF a-receptor overexpression (M. Nistr
and colleagues, in preparation). These observations may
imply that p53 mutations have an oncogenic effect only
in the presence of PDGF a-receptor overexpression. This
interdependence is highlighted by observations that mouse
astrocytes without functional p53 become transformed only
in the presence of specific growth factors 4.
display a remarkable tendency to infiltrate the surrounding
brain, confounding therapeutic attempts at local control.
These invasive abilities are often apparent in low-grade
as well as high-grade tumors, implying that the invasive
phenotype is acquired early in tumorigenesis. Investigations
into astrocytoma invasion have highlighted the complex
nature of cell-cell and cell-extracellular matrix interactions
8. A variety of cell surface molecules such as CD44 glycoproteins,
gangliosides and integrins are differentially expressed
in astrocytomas. Some, such as the A2B5 ganglioside, are
expressed primarily by non-dividing cells that are migrating;
others appear somewhat specific for neoplastic astrocytes.
Many of the growth factors expressed in astrocytomas,
such as FGF, EGF and VEGF, also stimulate migration 8.
common molecular changes also occur in grade II astrocytomas.
Loss of chromosome 22q, for instance, suggests the presence
of a chromosome 22q glioma tumor suppressor gene 9. While
the neurofibromatosis 2 (NF2) gene was a likely candidate
for this gene, NF2 mutations do not occur in astrocytomas
10 and deletion mapping of chromosome 22q in astrocytomas
has suggested a more telomeric locus.
to anaplastic astrocytoma
from WHO grade II astrocytoma to WHO grade III anaplastic
astrocytoma is accompanied by a marked increase in malignant
behavior. While many patients with grade II astrocytomas
survive for five or more years, patients with anaplastic
astrocytomas often die within two or three years and frequently
show transformation to GBM. Histologically, the major
differences between grade II and grade III tumors are
increased cellularity and the presence of mitotic activity,
implying that higher proliferative activity is the hallmark
of the progression to anaplastic astrocytoma.
of molecular abnormalities have been associated with anaplastic
astrocytoma, and recent studies have suggested that most
of these abnormalities converge on one critical cell-cycle
regulatory complex which includes the p16, cyclin-dependent
kinase 4 (cdk4), cyclin D1 and retinoblastoma (Rb) proteins.
The simplest schema suggests that p16 inhibits the cdk4/cyclin
D1 complex, preventing cdk4 from phosphorylating pRb,
and so ensuring that pRb maintains its brake on the cell
cycle 11. Individual components in this pathway are altered
in up to 50% of anaplastic astrocytomas and in the majority
9p loss occurs in approximately 50% of anaplastic astrocytomas
and GBMs, with 9p deletions occurring primarily in the
region of the CDKN2/p16 (or MTS1) gene, which encodes
the p16 protein 12. The frequency of 9p loss increases
not only at the transition from astrocytoma to anaplastic
astrocytoma, but also at the transition from anaplastic
astrocytoma to GBM, implying that the 9p tumor suppressor
plays a role in different stages of astrocytoma progression
13. While debate has raged on whether the CDKN2/p16 gene
is the primary glioma tumor suppressor gene on chromosome
9p, current evidence does implicate CDKN2/p16. Deletions
in primary GBMs almost always involve CDKN2/p16 12,14
and three mutations have been described in primary GBMs
with allelic loss of chromosome 9p 15-17. In addition,
reduced or absent p16 expression occurs in some malignant
gliomas without CDKN2/p16 loss 18, suggesting alternative
means, such as hypermethylation 19, of inactivating this
gene in GBMs. Moreover, replacement of CDKN2/p16 into
GBM cell lines lacking the gene results in growth suppression,
but had no effect in cell lines containing the CDKN2/p16
of chromosome 13q occurs in one-third to one-half of high-grade
astrocytomas, suggesting the presence of an progression-associated
astrocytoma tumor suppressor gene on that chromosome.
The 13q14 region containing the RB gene is preferentially
targeted by these losses and inactivating mutations of
the RB gene occur in primary astrocytomas 21. Overall,
analysis of chromosome 13q loss, RB gene mutations and
Rb protein expression suggests that the RB gene is inactivated
in about 20% of anaplastic astrocytomas and 35% of GBM
21. Interestingly, RB and CDKN2/p16 alterations in primary
gliomas are inversely correlated, rarely occurring together
in the same tumor 17.
amplification of the CDK4 gene and overexpression of cyclin
D1 may have similar effects to p16 or pRb inactivation
11, these mechanisms may provide additional alternatives
to subvert cell-cycle control and facilitate progression
to GBM 14. CDK4, located on chromosome 12q13-14, is amplified
in 15% of malignant gliomas 22, although this frequency
may be higher among cases without CDKN2/p16 loss, perhaps
reaching 50% of GBMs without CDKN2/p16 loss 14. CDK4 amplification
and CDKN2/p16 deletions do not occur together in GBM cell
lines and some GBM cell lines overexpress cyclin D1 23.
On the other hand, in some GBMs and GBM cell lines, CDK4
amplification and cyclin D1 overexpression appear to represent
alternative events to CDKN2/p16 deletions, since these
genetic changes only rarely occur in the same tumors 14,23.
In combination, it is likely that up to 50% of anaplastic
astrocytomas and perhaps all GBM have alterations in at
least one component of this critical cell-cycle regulatory
losses on 19q have been observed in up to 40% of anaplastic
astrocytomas and GBMs, indicating a progression-associated
glial tumor suppressor gene on chromosome 19q 24. This
tumor suppressor gene may be unique to glial tumors 25
and is involved in all three major types of diffuse cerebral
gliomas (astrocytomas, oligodendrogliomas, and oligoastrocytomas).
This gene maps to a region of chromosome 19q13.3, telomeric
to the marker D19S219 and centromeric to the HRC gene
26,27. A number of candidate genes have been isolated
from or mapped to this region 28, including the BAX gene,
whose product negatively regulates apoptosis with bcl-2,
but the tumor suppressor gene remains to be identified.
to glioblastoma multiforme
the most malignant stage of astrocytoma, with survival
times of less than 2 years for most patients. Histologically,
these tumors are characterized by dense cellularity, high
proliferation indices, endothelial proliferation and focal
necrosis. The highly proliferative nature of these lesions
is no doubt the result of multiple mitogenic effects.
As mentioned above, at least one such effect is deregulation
of the p16-cdk4-cyclin D1-pRb pathway of cell-cycle control.
The vast majority, if not all, GBM have alterations of
this system, whether it be inactivation of p16 or pRb
or overexpression of cdk4 or cyclin D1 14,17.
10 loss is a frequent finding in GBM, occurring in 60-95%
of GBMs but only rarely in anaplastic astrocytomas 9,29.
Attempts to identify this tumor suppressor gene by deletion
mapping, however, have been hampered by the observation
that, in most cases, the entire chromosome is lost. The
gene on the long arm may map to band q25 30-32. On the
other hand, there is probably a second tumor suppressor
gene on the short arm 29,32, and one study has postulated
that a third locus may exist on the long arm, near the
is a transmembrane receptor tyrosine kinase, whose ligands
include EGF and transforming growth factor-a. The EGFR
gene is the most frequently amplified oncogene in astrocytic
tumors 33, being amplified in approximately 40% of all
GBM 29 but in few anaplastic astrocytomas 34. Those GBMs
that exhibit EGFR gene amplification have almost always
lost genetic material on chromosome 10 29. GBMs with EGFR
gene amplification display overexpression of EGFR at both
the mRNA and protein levels, suggesting that activation
of this growth signal pathway is integral to malignant
progression to GBM 34,35. Approximately one-third of those
GBM with EGFR gene amplification also have specific EGFR
gene rearrangements, which produce truncated molecules
similar to the v-erbB oncogene. These truncated receptors
are capable of conferring dramatically enhanced tumorigenicity
to GBM cells 36. The downstream targets of EGFR activation
in GBMs are not well defined, but EGFR is most likely
involved in a cascade that facilitates mitogenesis in
tumor cells. Less commonly amplified oncogenes include
N-myc, gli, PDGF-a receptor, c-myc,
myb, K-ras, CDK4 and MDM2, some of which
have been discussed above.
above, one of the hallmarks of GBM is endothelial proliferation.
A host of angiogenic growth factors and their receptors
are found in GBMs. For example, VEGF and PDGF are expressed
by tumor cells while their receptors, flk-1 and flt-1
for VEGF and the PDGF b-receptor for PDGF, are expressed
on endothelial cells. VEGF and its receptors, in particular,
appear to play a major role in GBM angiogenesis 37,38.
A paracrine mechanism has been suggested in which VEGF
is secreted by tumor cells and bound by the VEGF receptors
on endothelial cells. Interestingly, VEGF is preferentially
upregulated by tumor cells surrounding regions of necrosis,
perhaps as a result of necrosis-induced hypoxia, since
hypoxia can upregulate VEGF. A link between p53 and tumor
angiogenesis has been suggested by the observations that
some mutant p53 molecules can enhance VEGF expression
37 and that wild-type p53 regulates the secretion of a
glioma-derived angiogenesis inhibitory factor 39.
of glioblastoma multiforme
that all astrocytomas progress through distinct genetic
stages in a linear fashion is most likely an oversimplification.
Indeed, it appears as if there are biologic subsets of
astrocytomas which may reflect the clinical heterogeneity
observed in these tumors (Figure 2). For instance, GBMs
can be divided on the basis of molecular genetic analysis.
As stated above, loss of chromosome 17p and associated
p53 mutation occur in tumors with PDGF-a receptor overexpression
(M. Nistr and colleagues, in preparation), and EGFR
gene amplification occurs in tumors with loss of chromosome
10 29. However, EGFR gene amplification almost never occurs
in GBMs with loss of chromosome 17p: approximately one-third
of GBM have p53/chromosome 17p alterations, one third
have EGFR gene amplification, and one third have neither
change 40. Significantly, those GBMs with loss of chromosome
17p occur in patients younger than those characterized
by EGFR gene amplification 40,41. Recent experimental
data also supports this distinction by showing that p53
deficient cells are not transformed when cultured in the
presence of EGF, whereas they are transformed in the presence
of other growth factors 4. Primary GBMs with p53 mutations
may therefore not be expected to acquire EGFR gene amplification,
if activation of the EGF-EGFR system does not produce
a growth advantage in such cells.
pathway involving 17p loss may involve progression from
a lower-grade astrocytic lesion, since loss of chromosome
17p, p53 mutation and PDGF-a receptor overexpression occur
as commonly in lower-grade astrocytomas as in higher-grade
astrocytomas (see above). On the other hand, those GBM
with EGFR amplification may arise either de novo or
rapidly from a pre-existing tumor, without a clinically-evident,
preceding lower-grade astrocytoma. Interestingly, younger
age at initial diagnosis has been an important prognostic
parameter among patients with GBM, with younger patients
faring better than older patients 42. The predominance
of tumors with 17p loss in a younger population of astrocytoma
patients may therefore reflect the age-based difference
in prognosis. Indeed, in a few studies, patients with
p53 mutations had somewhat better prognoses than those
without p53 mutations 6,43. In addition, it is possible
that those patients with anaplastic gliomas and a previous
history of lower-grade glioma that do better clinically
("dedifferentiated GBM") 44 are the same subset
as those GBMs with 17p loss. Finally, those GBMs with
EGFR gene amplification appear to recur more quickly than
those GBM without EGFR gene amplification 45, further
suggesting that tumors with EGFR gene amplification are
more rapidly progressing lesions. The data suggest that
genetic analysis may begin to explain the clinical observations
concerning age differences in astrocytic tumors.
stem gliomas are a form of pediatric diffuse, fibrillary
astrocytoma that often follow a malignant course. Brain
stem GBMs share genetic features with those adult GBMs
that affect younger patients: frequent p53 gene and chromosome
17p alterations without EGFR gene amplification 46. Since
brain stem gliomas are predominantly tumors of childhood,
this may suggest a common oncogenic pathway for those
diffuse, fibrillary astrocytic tumors that affect younger
patients, regardless of their anatomic location. On the
other hand, there is considerable variation in the transcription
levels of particular growth factors and proto-oncogenes
in different normal glial cell populations 47 and certain
astrocytes may display differential susceptibilities at
different ages to the same genetic alterations.
xanthoastrocytoma (PXA) is a superficial, low-grade astrocytic
tumor that predominantly affects young adults. While these
tumors have a bizarre histological appearance, they are
typically slow-growing tumors that may be amenable to
surgical cure. Some PXAs, however, may recur as GBM. PXAs
may have p53 mutations, but the few documented mutations
have been somewhat different from those usually found
in diffuse, fibrillary astrocytomas 48. EGFR gene amplification
does not occur in PXAs, but GBMs that arise from PXAs
may display EGFR gene amplfication. On the other hand,
allelic losses of chromosomes 9, 10 and 19q are not observed
in PXA. Thus, the genetic events that underly PXA formation
and progression probably differ from those involved in
diffuse astrocytoma tumorigenesis 48.
astrocytoma is the most common astrocytic tumor of childhood
and differs clinically and histopathologically from the
diffuse, fibrillary astrocytoma that affects adults. Pilocytic
astrocytomas do not have the same genomic alterations
as diffuse, fibrillary astrocytomas. Because pilocytic
astrocytomas frequently affect patients with neurofibromatosis
1 (NF1) and the NF1 gene maps to chromosome 17q11.2, pilocytic
astrocytomas may be expected to show allelic loss of chromosome
17q. In fact, allelic loss occurs on chromosome 17q in
one-quarter of cases 49. These data suggest the presence
of a tumor suppressor gene on 17q that is associated with
pilocytic astrocytomas. While the logical candidate for
this gene is the NF1 tumor suppressor gene, detailed mutational
analysis of the NF1 gene in pilocytic tumors has not yet
giant cell astrocytomas (SEGA) are periventricular, low-grade
astrocytic tumors that are usually associated with tuberous
sclerosis (TS), and are histologically identical to the
so-called "candle-gutterings" that line the
ventricles of TS patients. Similar to the other tumorous
lesions in TS, these are slowly-growing and may be more
akin to hamartomas than true neoplasms. The association
of SEGA with TS leads to the prediction that the TS genes
may be involved in SEGA formation. Linkage studies have
identified the location of two TS genes, one on chromosome
9q and another on chromosome 16p. Loss of heterozygosity
studies have shown allelic loss of chromosome 9q and 16p
loci in some SEGAs, suggesting that the TS genes act as
tumor suppressors 50,51. However, confirmation of the
role of the TS genes in glial tumorigenesis must await
mutational analysis of these genes in cases of SEGA.
cerebral astrocytoma of infancy (DCAI) and desmoplastic
infantile ganglioglioma (DIGG) are large, superficial,
usually cystic, benign astrocytomas that affect children
in the first year or two of life. Allelic loss of chromosomes
10 or 17 is not common in these lesions 52. In adult gangliogliomas,
another benign form of astrocytic glioma, EGFR gene amplification
or allelic loss on chromosomes 10, 13q, 17p, 19q and 22q
has not been detected (A von Deimling and DNL, unpublished
and oligoastrocytomas (mixed gliomas) are diffuse, usually
cerebral tumors that are clinically and biologically most
closely related to the diffuse, fibrillary astrocytomas.
The tumors, however, are far less common than astrocytomas
and have generally better prognoses than the diffuse astrocytomas;
patients with WHO grade II oligodendrogliomas, for instance,
may have mean survival times of 10 years. In addition,
oligodendroglial tumors appear to be differentially chemosensitive
53, when compared with the diffuse astrocytomas.
losses in oligodendrogliomas and oligoastrocytomas occur
preferentially on chromosomes 1p and 19q, affecting 40-80%
of these tumor types 24,54,55. Because of the frequent
loss of these loci in low-grade as well as anaplastic
oligodendrogliomas and oligoastrocytomas, the 1p and 19q
tumour suppressors are probably important early in oligodendroglial
tumorigenesis. Mapping of the chromosome 19q locus has
demonstrated that the gene resides in the same vicinity
as the astrocytoma gene, between APOC2 and HRC, and is
likely the same gene 26,27. Similar mapping of chromosome
1p has implicated the telomeric region of 1p32-36 55.
Interestingly, chromosome 1p and 19q losses are closely
associated; oligodendroglial tumours with 1p loss typically
also have loss of 19q, suggesting that these two putative
tumour suppressor genes may be involved in biologically
distinct pathways 54,55. In fact, microdissection of the
oligodendroglial and astrocytic components in oligoastrocytomas
has shown that, despite the histological differences,
the molecular changes are identical in these two components
55. Oligoastrocytomas in particular may also suffer allelic
losses of chromosome 17p 54, although these losses are
not associated with p53 mutations 54,56, perhaps implying
a second chromosome 17p glioma gene. Oncogene amplification
has only rarely been noted in oligodendroglial tumours
and oligoastrocytomas may progress, either to WHO grade
III anaplastic oligodendroglioma or anaplastic oligoastrocytoma,
or to WHO grade IV GBM. Thus, the genetic changes that
lead to oligodendroglial tumors constitute yet another
pathway to GBM (Figure 2). Anaplastic oligodendrogliomas
and oligoastrocytomas may display allelic losses of chromosomes
9p and 10 54 and allelic loss of chromosome 10 may be
a common finding in high-grade malignant gliomas, whether
they are astrocytic or oligodendroglial in original lineage
9. At least one aggressive oligodendroglioma with allelic
loss of chromosome 10 rapidly recurred as a GBM 57.
and choroid plexus tumors
are a clinically diverse group of gliomas that vary from
aggressive intraventricular tumors of children to benign
spinal cord tumors in adults. Chromosome 22q loss is common
in ependymomas 58,59. A candidate glioma tumor suppressor
gene on chromosome 22q was the neurofibromatosis 2 (NF2)
gene 60, since NF2 patients have a higher incidence of
gliomas, particularly ependymomas, in addition to schwannomas
and meningiomas. Analysis of the NF2 gene in ependymomas,
however, has revealed only a single mutation to date,
in an ependymoma that had lost the remaining wild-type
allele 10. The paucity of NF2 mutations suggests that
another, as yet unidentified, chromosome 22q gene will
probably be a more integral ependymoma locus. The p53
gene is not mutated in ependymomas 56 or in the malignant
transformation of ependymomas to anaplastic ependymoma
(S. Cortez and DNL, unpublished data). Transitions of
ependymoma to GBM are rare, and have not been studied
by molecular genetic techniques.
plexus tumors are also a varied group of tumors that preferentially
occur in the ventricular system, ranging from aggressive
supratentorial intraventricular tumors of children to
benign cerebellopontine angle tumors of adults. Choroid
plexus tumors have been reported occasionally in patients
with Li-Fraumeni syndrome and von Hippel-Lindau (VHL)
disease (as well as in Aicardi syndrome, which does not
predispose to cancer), raising the possibility that the
p53 gene on chromosome 17p, responsible for Li-Fraumeni
syndrome, or the VHL gene on chromosome 3p is involved
in choroid plexus neoplasia. Loss of chromosome 3p sequences
have been found in one choroid plexus tumor, suggesting
involvement of the VHL gene 61.
viruses may cause human cancer, particularly those viruses
whose products interfere with tumor suppressor gene functions,
such as the human papillomaviruses implicated in cervical
carcinoma. One study has identified sequences similar
to SV40 virus, an oncogenic virus that has the ability
to inactivate both the Rb and p53 proteins, in human ependymomas
and choroid plexus papillomas 62. This observation raised
considerable excitement since SV40 has been implicated
as an oncogenic factor in transgenic models of choroid
plexus neoplasia 63. However, SV40-like sequences have
not been found in other choroid plexus papillomas or ependymomas
and the role of oncogenic viruses in these tumors remains
are highly malignant, primitive tumors that arise in the
posterior fossa, primarily in children. One third to one
half of all medulloblastomas have an isochromosome 17q
on cytogenetic analysis 64, and corresponding allelic
loss of chromosome 17p has been noted on molecular genetic
analysis 65,66. Initially, this suggested involvement
of the p53 gene, but p53 mutations have proven to be very
rare in medulloblastomas 56,67. Allelic losses occur preferentially
at regions of chromosome 17p that are telomeric to the
p53 locus 66,68, implying the presence of a second, more
distal chromosome 17p tumor suppressor gene. Allelic losses
of chromosome 6q, 11 and 16q have also been noted frequently
in these tumors 65. Deletions of the CDKN2/p16 gene, which
are common in many tumors, do not occur in medulloblastomas
69. Oncogene amplification has not been found frequently
in medulloblastomas; only c-myc is amplified in significant
numbers of cases and this change appears more common in
medulloblastoma cell lines than in primary tumors 64.
are common intracranial tumors that arise in the meninges
and compress the underlying brain. Meningiomas are usually
benign, but some "atypical" meningiomas may
recur locally, and some meningiomas are frankly malignant
and may invade the brain or metastasize. Monosomy 22 is
common in meningiomas, pointing to a chromosome 22q meningioma
suppressor gene. Indeed, the neurofibromatosis 2 (NF2)
gene on chromosome 22q is frequently mutated in meningiomas,
clearly implicating it in meningothelial tumorigenesis
70-72. In sporadic meningiomas, both chromosome 22q allelic
loss and NF2 gene mutations are more common in fibroblastic
and transitional subtypes than in meningothelial forms
71. As in schwannomas (see below), NF2 gene alterations
result predominantly in immediate truncation, splicing
abnormalities or altered reading frames, producing grossly
truncated proteins. Interestingly, NF2 gene mutations
in meningiomas cluster in the moesin-ezrin-radixin homology
domain in the first half of the coding sequence 71,72.
40% of meningiomas have neither NF2 gene mutations nor
allelic loss of chromosome 22q. For these tumors, it is
likely that a second meningioma tumor suppressor gene
is involved. This putative second gene is probably not
on chromosome 22q, since NF2 gene mutations in meningiomas
correlate fairly closely with chromosome 22q loss. Nonetheless,
a few meningiomas have been described with loss of portions
of chromosome 22q that do not include the NF2 gene, suggesting
the possibility of a second meningioma locus on chromosome
22 73. One candidate gene from this second chromosome
22q region is BAM22, a member of the b-adaptin gene family,
which may be inactivated in some sporadic meningiomas
74. Another candidate is the MN1 gene, which is disrupted
by a translocation in a meningioma 75. Furthermore, a
family with multiple meningiomas but without vestibular
schwannomas does not show linkage to the NF2 locus on
chromosome 22q, suggesting yet another meningioma predisposition
gene 76. Allelic losses in meningiomas have been noted
on a variety of other chromosomes, including 1p3, 3p,
5p, 5q, 11, 13 and 17p 77.
and malignant meningiomas are not as common as benign
meningiomas. Genetic analyses of malignant meningiomas
have revealed preferential losses of chromosomes 1p, 10
and 14q 78,79. In one anaplastic meningioma, molecular
genetic analysis of three morphologically distinct regions
revealed loss of heterozygosity for chromosomes 1p and
22q in all regions, but for chromosomes 17p and 9q only
in the malignant region 78. Chromosome 10 loss, in particular,
has been associated with those meningiomas with morphological
features of malignancy, rather than those meningiomas
which are designated as malignant on the basis of brain
invasion alone 79.
are benign tumors that arise on peripheral nerves. Schwannomas
may arise on cranial nerves, particularly the vestibular
portion of the eighth cranial nerve (vestibular schwannomas,
acoustic neuromas) where they present as cerebellopontine
angle masses. NF2 patients are defined by the presence
of bilateral vestibular schwannomas 80, although unilateral
vestibular schwannomas are common in the general population
as well. Therefore, like meningiomas, schwannomas occur
frequently in NF2 patients, have frequent loss of chromosome
22q, and harbor NF2 gene mutations in at least 50% of
cases, in vestibular tumors as well as schwannomas from
other sites 80. A detailed analysis of a cohort of 60
vestibular schwannomas using combined screening methods
has revealed mutations in the vast majority of schwannomas
(L.B. Jacoby, personal communication). The majority of
the somatic changes are small deletions or insertions
that create either frameshifts and premature stop codons
or altered splicing. Inactivating mutations are relatively
evenly distributed across the first 15 exons with no outstanding
hot spots. One study has confirmed such inactivation at
the protein level, showing loss of merlin expression by
immunohistochemistry in schwannomas 81. Thus, inactivation
of NF2 is a common feature underlying both inherited and
sporadic forms of schwannoma.
are tumors of uncertain origin that are composed of endothelial
cells, pericytes and so-called stromal cells. These benign
tumors most frequently occur in the cerebellum and spinal
cord of young adults. Multiple hemangioblastomas are characteristic
of von Hippel-Lindau disease (VHL), an inherited tumor
syndrome in which patients have a tendency to develop
tumors, particularly hemangioblastomas, retinal angiomas,
renal cell carcinomas and pheochromocytomas 82. Because
of the association of VHL and hemangioblastomas, studies
of hemangioblastomas have focussed on the VHL gene.
gene was originally mapped by linkage analysis to chromosome
3p 83 and allelic loss studies of hemangioblastomas are
consistent with this location 84. The gene responsible
for VHL has been identified 85 and is mutated in sporadic
hemangioblastomas 86, suggesting that the VHL gene acts
as a classical tumor suppressor and is involved in both
sporadic hemangioblastomas and familial tumors.
(HPCs) are dural tumors which may display locally aggressive
behavior and may metastasize. The histogenesis of dural-based
hemangiopericytoma (HPC) has long been debated, with some
authors classifying it as a distinct entity and others
classifying it as a subtype of meningioma. In constrast,
meningiomas contain frequent mutations of the NF2 gene,
while HPCs do not, suggesting that HPC is genetically
distinct from meningioma 87. In addition, homozygous deletions
of the CDKN2/p16 gene are common in HPCs, and suggest
that alterations of the p16-mediated cell-cycle regulatory
pathway may underlie the malignant potential of some HPCs
88. Rearrangements of chromosome 12q13 are common in peripherally
located, soft tissue HPCs and have been reported in meningeal
HPCs, implying that an oncogene or tumor suppressor gene
at this locus is important in HPC formation. A number
of oncogenes reside in this region, including MDM2, CDK4
and CHOP/GADD153. Interestingly, CHOP/GADD153 amplification
and constitutive expression has been noted in at least
one soft tissue HPC 89.
Neurological tumor syndromes
neurological tumor syndromes, in which patients are at
risk for developing multiple nervous system tumors, have
provided important clues to the genetic basis of brain
tumors. These tumor syndromes provide unique insights
into tumor suppressor genes. For instance, the hereditary
retinoblastoma syndrome, which provided much of the impetus
for current tumor suppressor gene research, results from
a mutation in both Rb tumor suppressor alleles 90. In
the case of familial retinoblastoma, the patient inherits
one mutant, inactive copy of the retinoblastoma gene and
thus carries a "germline" mutation in every
cell 91, which is unveiled when the second copy of the
gene is inactivated, either by mutation or by loss of
a portion of chromosome 13q. A patient with sporadic retinoblastomas
does not carry the germline mutation and must acquire
both inactivating "hits" in the same cell during
his or her life. Therefore, a familial retinoblastoma
patient, in which every cell contains a mutation, is much
more likely to develop a second retinoblastoma than a
sporadic retinoblastoma patient 92. This same paradigm
appears to hold true for most, but not all 93, of the
hereditary tumor syndromes.
tumor syndromes include the so-called neurocutaneous syndromes,
such as neurofibromatosis 1 (NF1), neurofibromatosis 2
(NF2), tuberous sclerosis (TS), and von Hippel-Lindau
disease (VHL), and other tumor conditions such as Li-Fraumeni,
Turcot's, Gorlin's and Cowden's syndromes. Each syndrome
is accompanied by a characteristic panoply of tumors,
both neurological and non-neurological. A catalogue of
only the gliomas would feature optic nerve gliomas and
other astrocytomas in NF1; ependymomas and astrocytomas
in NF2 ; subependymal giant cell astrocytomas in TS; and
various malignant gliomas in Li-Fraumeni syndrome, Turcot's
syndrome and the hereditary glioma pedigrees. Linkage
studies have provided powerful means for tracking down
the genes associated with these tumor syndromes, and have
assigned the NF1 gene to chromosome 17q; the NF2 gene
to chromosome 22q; the TS genes to chromosome 9q and 16p;
Turcot's genes to chromosome 5q (APC gene) and to the
DNA mismatch repair genes on various chromosomes. The
NF1 gene codes for a guanosine triphosphatase-activating
protein (GAP) termed neurofibromin. Neurofibromin interacts
with the p21 product of the ras oncogene and is
most likely important in growth factor-mediated signal
transduction. The NF2 gene codes for a protein, termed
merlin, that is homologous with moesin, ezrin and radixin,
suggesting that the protein functions to link the cytoskeleton
and cell surface. One of the TS genes, TSC2 on chromosome
16p, has also recently been identified. Like NF1, TSC2
encodes a GAP protein. While TSC2 GAP is not homologous
with neurofibromin, these proteins may nonetheless be
involved in similar cellular pathways . For the Li-Fraumeni
syndrome, mutational analyses have implicated the p53
gene on 17p. The other neurological tumor syndromes, their
chromosomal locations, known genes and putative functions
are catalogued in Table 2 and have been the subjects of
recent reviews 80,82,93-95.
brain tumors have molecular alterations that are characteristic
of each type of tumor and of most stages of progression.
For instance, the formation of grade II astrocytoma involves
inactivation of the p53 tumor suppressor gene on chromosome
17p, as well as PDGF overexpression, loss of a putative
tumor suppressor gene on chromosome 22q, and the expression
of various molecules that facilitate tumor invasion. The
transition from astrocytoma to anaplastic astrocytoma
is associated with alterations of the critical cell-cycle
regulatory pathway that includes p16, cdk4, cyclin D1
and Rb, as well as a putative tumor suppressor gene on
chromosome 19q. Finally, progression to GBM involves loss
of a at least one putative tumor suppressor gene on chromosome
10, amplification of the EGFR gene and the expression
of angiogenic factors such as VEGF. Furthermore, molecular
genetic analysis has been used to distinguish subsets
of astrocytomas. For instance, one type of GBM, characterized
by p53 gene mutations, is more common in younger patients
and may be associated with slower progression from lower-grade
astrocytoma; another type of GBM, characterized by EGFR
gene amplification, is more common in older patients and
may be associated with more rapid progression or "de
less common gliomas and for other primary tumors such
as medulloblastomas, molecular genetic studies have defined
only isolated genetic alterations. For meningiomas and
schwannomas, the NF2 gene has been clearly implicated,
although other genetic alterations must underlie the formation
of some meningiomas as well. For those tumors associated
with hereditary tumor syndromes, such as the SEGAs in
TS and the hemangioblastomas in VHL, the same genes appear
responsible for the syndromes when mutated in the germline,
and for sporadic tumors when mutated on a somatic basis.
At the present time, however, these molecular data are
incomplete. Once the molecular pathways are completely
understood, such knowledge will no doubt contribute to
the development of more effective therapies for many of
these tumors .
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