Genetics of Adult Malignant Gliomas
Joan Rankin Shapiro, PhD
Stephen W. Coons, MD*
Divisions of Neurology and *Neuropathology, Barrow Neurological Institute, St. Joseph’s Hospital and Medical Center, Phoenix, Arizona
The genetic aberrations responsible for the formation and progression of malignant gliomas are being identified. It is now possible to correlate some of these aberrations with the specific histopathological and biologic characteristics of astrocytic tumors, oligodendrogliomas, and ependymomas. In defining these progressive alterations, distinctions that are unique to different types of gliomas are being identified as well as potential subsets within specific types of gliomas. This article reviews the genetic changes associated with malignant gliomas. Many of these alterations are being investigated for their potential as diagnostic and prognostic indicators and as new therapeutic targets.
Key Words : astrocytomas, ependymomas, oligodendrogliomas, oncogenes, tumor suppressor genes
Technical advances and hereditary cancers have increased our understanding of the genetic aberrations associated with brain tumors. Genetic cancers have provided insight into the multiple steps required to immortalize a cell, to allow its uncontrolled proliferation, and to invade and modulate the local cellular environment.14,16,32 Brain tumors likewise develop in a multiple step process. From these new findings, models of tumor progression are being developed in which genetic lesions are being associated with specific tumor types and pathological grades.41,84,179
Diffuse astrocytomas are the most common type of glioma in both adults and children. Adult and pediatric tumors, however, exhibit several notable differences besides histology. The first is a predilection for different locations in the brain. Adult brain tumors tend to develop supratentorially within the cortical, subcortical, and basal ganglia regions. In contrast, about 60% of pediatric tumors develop infratentorially within the cerebellum, pons, and brain stem.147 The incidence of particular tumor types also differs. Astrocytic tumors, oligodendrogliomas, and ependymomas are most common in adults while pilocytic astrocytomas and primitive neuroectodermal tumors (PNET) are more common in children.
The response of adult and pediatric malignancies to therapy also differs.155 Extensive resection, irradiation, and chemotherapy improve survival only modestly in adults with malignant central nervous system (CNS) tumors.154 Pediatric tumors tend to be more responsive to treatment, especially to chemotherapy.56 This differential responsiveness may reflect biological differences in adult and pediatric tumors, even when they appear to be the same histological type and grade. Thus, there is a need to determine if alternative pathways of evolution exist within tumor types and between adults and pediatric brain tumors.Figure 1. Chart illustrating normal brain, progressive forms of astrocytomas (Grade II to Grade IV), and associated genetic lesions. GBM = glioblastoma multiforme..
Typically, astrocytomas (grade II tumors) occur in individuals between 20 and 40 years old. They tend to grow slowly but are not benign because of their invasive quality and location. Fibrillary astrocytomas can occur anywhere in the brain but are most prevalent in the cerebral hemispheres. Their histology lacks nuclear atypia and mitotic activity. Low-grade tumors are difficult to study because of tissue availability. Needle biopsies are often used to make a diagnosis. Upon resection, these tumors are frequently admixtures of normal reactive cells and tumor cells. The proportion of normal cells to tumor cells can greatly influence experimental results.19,22 The tumors can also appear to be mixtures of different histological grades of tumor. These complexities raise questions about whether low-grade gliomas are cytogenetically normal with molecular genetic lesions, whether specific numerical abnormalities reflect a specific pathway of tumor evolution, or both.84
The cytogenetics of astrocytic tumors is reviewed extensively elsewhere.153 The most common numerical aberration involves the gain of chromosome 7 along with the loss of a single sex chromosome. Structural abnormalities are rare but involve chromosomes 1p and 9p153 when observed.
Mutations and allelic loss (loss of one or both genes at a specific locus) have been the primary genetic lesions detected by molecular analyses. One of the early events in the formation of a malignant glioma involves a mutation or allelic loss of chromosome 17p (Fig. 1).35,36,40,59,60,72,86,100,143,156,175,177 The target gene in 17p is the TP53 gene in which more than 200 mutations have been described in human tumors.55 This gene may be important in both initiation and progression.71 Sequence data indicate that a highly conserved region involving exons 5, 7, and 8 bears the majority of missense mutations that inactivate the TP53 gene.85 A brain-specific mutation does not appear to exist. Most DNA lesions in the TP53 gene occur in the so-called “hot spots” involving codons 175, 248, and 273.23 These same abnormalities are associated with most other types of cancer.
The TP53 gene binds to DNA to control the transcription of other genes. Many of its identified mutations cause this function to be lost. The amplification of several oncogenes [e.g., murine double minute 2 (MDM2) or c-myc] also abrogates the function of p53.125,126MDM2 binds to p53 and inactivates it while c-myc enhances its expression.130 p53 protein also affects the expression of growth factors. For example, wild-type TP53 represses the basic fibroblast growth factor (bFGF) transcriptional promoter. This finding is supported by cells with mutated TP53, which exhibit an upregulation of bFGF.169 A similar scenario may exist with vascular endothelial growth factor (VEGF), a mediator of angiogenesis.68 With VEGF these events may be more critical in higher grade tumors because the histopathology of astrocytomas does not support the complete loss of cell cycle control or angiogenesis in lower grade neoplasms.84,190
Mutant TP53 is identified in more than a third of the astrocytomas. It may be important in the genesis of low-grade astrocytomas by abrogating apoptosis or by increasing genomic instability. Of interest is the frequency of TP53 abnormalities in different age groups. TP53 mutations appear to be more common in patients between 18 years and the mid 40s (44%) than in older patients (9%).119,181Consequently, TP53 mutations may follow a different evolutionary pathway in younger patients than in older patients. This phenomenon is discussed in greater detail in the section on glioblastomas multiforme (GBMs).Figure 2. The retinoblastoma gene (RB) inhibits the progression of the cell cycle for G0/G1 S, and several positive and negative regulators control this gene. Although this illustration represents only one of many genes that affect the cell cycle, it demonstrates how multiple genes are involved in a single pathway and how the deregulation of any one gene can produce a similar phenotype. The shaded blocks show inhibition. The solid arrows show the genes that are responsible for activation. The enclosed boxes with dashed arrows show the chromosomal locations of the genes. All these chromosome regions are regions that are involved in chromosomal abnormalities. WAF is an alternate name for CDKN1, and MTS1 and p16 are former names for CDKN2.
A second family of genes important in astrocytomas includes the platelet-derived growth factors A and B (PDGFA and PDGFB) and PDGF receptors a and b (PDGFR-a and PDGFR-b) (Fig. 1).191 The PDGFA and B chains dimerize to form AA, BB, or AB homo- or heterodimers. The receptor, PDGFR-a, binds with AA and AB while PDGFR-b binds with BB. In astrocytomas, the A chain and a-receptor are predominantly overexpressed.34,51,52,102 This observation is interesting because the most common chromosomal abnormality identified in astrocytomas involves aneuploidy of chromosome 7,10 the chromosomal location of the PDGF-A chain. In vitro and in vivo, treatment with 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU) selects for a minor subpopulation of cells containing amplified PDGF-A and -B chains.145 Changes in the expression of growth factors and their receptors may also initiate local environmental changes that begin to stimulate angiogenesis. Overexpression of PDGFR also correlates with the loss of heterozygosity for 17p.52 Although the exact nature of these events is unknown, PDGF and its receptors clearly play a role in tumor evolution.
In about 30% of the astrocytomas, allelic loss has been identified on chromosome 22q.38,59,99 A likely candidate for this genetic loss was the NF-2 gene, but an extensive analysis of this gene in all grades of gliomas failed to detect a consistent abnormality.54,138Allelic loss on chromosome 22q occurs more telomeric to the NF-2 gene,120,134 but the gene or genes involved have not been identified. Other chromosomes exhibiting allelic loss in astrocytomas include chromosome 1,9,49,174 chromosome 3,61 and chromosome 13.121 Each allelic loss identified in these studies represents a probable site for tumor suppressor genes but awaits confirmation.
Anaplastic astrocytomas are thought to develop from low-grade astrocytomas (Fig. 1).15,140 Although no sharply defined histological criteria separate astrocytomas from anaplastic astrocytomas, the latter are distinguished by a high cell density and level of mitotic activity, early or focal contrast enhancement, and a high degree of nuclear polymorphism including multinucleation, lobulation, and angulation.140 The nuclear-cytoplasmic ratio is also increased, but the astrocytic character is still evidenced by fibrillar eosinophilic cytoplasm and the presence of processes.
Anaplastic astrocytomas occur in both young and old patients, but their incidence peaks in the mid50s. Like astrocytomas the gain of chromosome 7 is the most frequent numerical aberration. Chromosomes 19 and 20 also tend to be overrepresented while the chromosomes most frequently lost are chromosomes 10, 22, and a single sex chromosome. The patterns of gain and loss are more prominent in anaplastic astrocytomas as are the numbers of structural abnormalities. Most breakpoints occur on the p arms of chromosomes 1, 3, and 9 (1p32, 1p36, 3p21, 9p21 and 9p22) with similar clusters in the q arms of chromosomes 6 and 7 (6q21 and 7q22) and occasionally in chromosomes 5p13, 15q11, 17p11, and 19q12.1.153
Thirty to forty percent of the anaplastic astrocytomas have a mutation of the TP53 gene (17p13.1) in addition to allelic loss, overexpression of PDGF and PDGF receptors, and allelic loss on 22q.29,35,36,38,59,72,74,86,124,143,156,173,175 Changes that mark the transition from astrocytoma to anaplastic astrocytoma involve allelic loss on 9p, 11p, 13q, and 19q. The changes associated with chromosomes 9 and 13 are important steps in the evolution of this tumor because the target genes are proteins that govern critical steps in the cell cycle.
A key gene in this scenario is the retinoblastoma gene (RB) located on chromosome 13q14. The protein encoded by this gene is a checkpoint in the cell cycle that inhibits the transition of the G0/G1®S phase (Fig. 2). When the Rb1 protein is phosphorylated by either CDK4/CDK6 or CDK2, it becomes inactivated and no longer inhibits G1®S. The CDK4/CDK6 and CDK2 genes are controlled by positive (cyclins D1 and E) and negative (CDKN2/p16 or p21 proteins) regulators. The deregulation of either of these genes or genes upstream in the pathway can produce a similar loss of control over the cell cycle.
The function of upstream genes exerting control over CDKN2/p16 and p21 can also be abnormal (Fig. 2). For example, activation of the CDKN1/WAF1 gene, which is under the control of the p53 protein, results in the production of the p21 protein. Wild type p53 protein can be suppressed by the amplification of the oncogene MDM2 or upregulated by c-myc (Fig. 2). Thus, the cascade of events leading to the inhibition of the Rb1 protein is controlled by multiple genes. If any one gene fails to function normally, the cell cycle continues unchecked. In fact, more than one DNA lesion in the critical steps of this cell cycle pathway may be rare.50,170 However, it is possible to use two different markers to determine aberrancy within the cell cycle. For example, comparisons of allelic loss in an inhibitor such as CDKN2/p16 and the proliferative marker Ki-67 demonstrate a distinct relationship. When there is a homozygous deletion of the inhibitor CDKN2/p16, proliferation correspondingly increases.109
Not all deregulation is related to the allelic loss of genetic material. Several investigations have identified a region on chromosome 12 (12q13-14) that is amplified in 15% of World Health Organization grade III (anaplastic astrocytomas) and grade IV (GBMs) tumors.119,126 A number of genes map to this region. Two (i.e., MDM2 and CDK4) are frequently amplified and can deregulate the cell cycle (Fig. 2).25 MDM2 codes for a cellular protein that complexes with the p53 tumor suppressor gene product and inhibits its function. Gliomas, in which TP53 is seldom lost or mutated, can thereby escape TP53-mediated growth regulation.119,126Chromosome 9q21, the map location for CDKN2/p16,63,108 is a region of frequent allelic loss. The loss of this inhibitor104,172 provides an alternative mechanism leading to the same biological endpoint—an increase in CDK4.
Allelic loss on chromosome 19q13.2-13.3 has been observed, although the putative tumor suppressor gene has not yet been identified.135,139,178,180 This gene, which appears to be unique to glial tumors, is the only allelic loss shared by astrocytic tumors, oligodendrogliomas, and oligoastrocytomas (discussed below). Several candidate genes cloned from this chromosome region are under active investigation.171,198
Multiple deletions and rearrangements have also been noted on chromosome 1.153 Analysis of this chromosome has recently discovered a family member of the TP53 gene. Regions spanning 1p36-p32, a site involved in numerous deletions and translocations, demonstrate frequent allelic loss.7,9 Although small, the sampling of anaplastic astrocytomas has detected allelic loss in this region. This finding suggests that the new p73 gene, a gene that is 63% homologous to TP53 in the DNA-binding regions, will function much like TP53.65,66
Other chromosomes identified as having allelic loss include chromosome 11p15®pter39,159 and chromosome 3p21.73 More anaplastic astrocytomas must be analyzed to determine the importance of these findings.
GBMs are the most malignant of the astrocytic tumors. The mean survival time of patients with this diagnosis is about 1 year (Fig. 1).155 GBMs are highly infiltrative, producing undifferentiated elements as a dominant feature in addition to mitotic activity and necrosis. Vascular proliferation may also be evident, along with a high bromodeoxyuridine/Ki-67 labeling index. Although the genetic instability of this tumor creates numerous and varied genetic changes, malignant astrocytic gliomas develop several nonrandom chromosome changes that are associated with progression.153 The most frequent numerical chromosome changes involve the gain of chromosomes 7 and 20 and the loss of chromosomes 10, 22, and a single sex chromosome as reviewed elsewhere.153 The gain of chromosome 20 is more numerous in GBMs than in anaplastic astrocytomas. In general, numerical changes appear to reflect loss more than gain of chromosomes (e.g., the loss of chromosomes 9, 13 and 14).
GBMs represent about 50% of all intracranial neoplasms. Tissue availability is less of a factor than it is with astrocytomas, and a large amount of molecular data has been generated on this tumor. The frequency of TP53 mutations and/or allelic loss is about the same in GBMs as in anaplastic astrocytomas and astrocytomas. This finding supports the hypothesis that this DNA lesion is an early change in the evolution of gliomas.59 The clonal expansion of a TP53 mutation as the dominant cellular population in a recurrent tumor further supports this hypothesis.156 Another gene independent of TP53, however, may reside at 17p13.3.17
Other significant DNA lesions are associated with the gain of chromosome 7. The genes encoding the epidermal growth factor receptor (EGFR) and the A chain of PDGFA are mapped to chromosome 7 at 7p13-p11 and 7q11-q13, respectively. Both of these genes are amplified or overexpressed in GBMs.10,51 More than half of the GBMs with an amplification of EGFR also have a rearrangement of the gene.27 This mutated form of the EGFR has a high level of tyrosine kinase activity in the absence of the EGF ligand, essentially keeping this receptor in a “turned on” autocrine mode.24 PDGF may be overexpressed less often in GBMs, but its autocrine regulation suggests that like EGFR it could provide a selective growth advantage to tumor cells.
Figure 3 is a hypothetical version of how growth factors and growth factor receptor signaling affect cellular proliferation. Almost every growth factor known to stimulate cell division has been identified as aberrantly expressed in GBM cell lines and fresh tissue.12 Growth factors, such as PDGFA, PDGFB, EGF, transforming growth factor-a and -b (TGF-a and TGF-b), VEGF, insulin-like growth factor (IGF-I and IGF-II), bFGF, and their receptors, are necessary components of an organism during normal development and body function188and in pathology.12 Most of these growth factors have receptor tyrosine kinase activity. The kinase adds phosphate groups to the intracellular domain of the receptor and activates it to initiate the cascade of signals that makes cells divide. The aberrant function of one or more of these factors in gliomas is thought to be one of the major reasons that control of the growth stimulatory pathways is lost. The identification of the tumor suppressor gene (PTEN/MMAC-1, phosphate-tensin/mutated in multiple advanced cancers-1) on chromosome 10q23.3 further strengthens this hypothesis.80,162Figure 3. Illustration showing how aberrant expression of several growth factors can influence the growth stimulatory pathways by activating transcription. Tumor cells show amplification of receptors for EGF and PDGF and less frequently FGF and IGF(not shown). The EGF receptor (EGFR) can bind either TGF-a or its normal ligand, EGF. Typically, TGF-a is only produced by tumor cells. The dotted arrows indicate that once the receptors are activated, they send a second messenger to the nucleus to activate transcription factors that produce specific mRNAs, triggering cell division.
Significant loss of the whole chromosome 10 has been found in about 50% of the GBMs analyzed cytogenetically. Allelic loss on chromosome 10p and 10q occurs in as many as 60 to 90% of the gliomas.18,37,67,123 The PTEN/MMAC-1 gene encodes a tyrosine phosphatase, a molecule whose opposing enzymatic activity removes phosphate groups. Among the genes encoding receptor tyrosine kinase activity, two (EGFR and PDGF) are often aberrant in gliomas. EGFR can bind both its ligand EGF and TGF-a (Fig. 3). Because this receptor is the most frequently amplified gene in GBMs,81,195 the amplification-associated overexpression of EGFR could potentially override the normal negative regulation of the PTEN/MMAC-1 gene product.163
In contrast, GBM cells with homozygous deletion, mutation, or both will have an inactivated PTEN/MMAC-1 gene that will completely eradicate the negative regulatory activity.162 Mutation or loss of the PTEN/MMAC-1 gene product is almost exclusively limited to GBMs,122,184 and these aberrations appear to occur at the same frequencies whether EGFR is amplified or not.83 Additional tumor suppressor genes might therefore reside on chromosome 10 besides PTEN/MMAC-1.1,69,160,161 About 30 to 50% of gliomas also have a deletion of the extracellular domain of EGFR.101 This deletion results in a truncated receptor that is constitutively active in which signals are continually sent to the nucleus to initiate proliferation.Figure 4. Illustrations showing the autocrine and paracrine mechanisms associated with human gliomas. Each growth factor can initiate an autocrine, paracrine, and/or exocrine influence that will stimulate both normaland tumor astrocytes. The stimulatory behavior also affects endothelial, smooth muscle, and meningeal cells.
PDGF and its receptors differ from EGFR in that they have few mutations. Most GBMs, however, overexpress at least one PDGF chain and its respective receptor, and the most common form of overexpression is the PDGFA chain and PDGF-a receptor (Fig. 3).45,48 The PDGF-a receptor can bind all three isoforms, suggesting that an autocrine loop forms (Fig. 4) for this growth factor similar to the autocrine behavior of EGFR. Immunohistochemistry and in situ hybridization have clarified that the PDGFA chain and the PDGF-areceptor are preferentially expressed in tumor cells whereas the PDGFB chain and the PDGF-b receptor are highly expressed in proliferating endothelial cells within the tumor.51,53,115 Normal brain tissue also expresses the PDGF-b receptor and the PDGFA chain; however, the PDGF-b receptor will only bind the PDGFB chain so it is inactive in normal brain.91 Consequently, the preferential expression of the PDGF-b receptor in the endothelial component of gliomas may be related to the angiogenesis observed in these high-grade tumors.116
Other types of genes are also aberrant in GBMs and might contribute to their malignant and invasive phenotype. How these genes accomplish that task is undefined. For example, the DCC (deleted in colon cancer) gene is mapped to chromosome 18q21.31 The gene is a transmembrane cell adhesion molecule of the neural cell adhesion molecule (NCAM) family. As its name implies, DCC was discovered in colon cancer. High-grade gliomas exhibit abnormalities of chromosome 18, and several molecular studies have indicated that it is deleted in GBMs28,144 and in some Grade II tumors.144 Cell guidance molecules may therefore be involved in tumorigenesis.30 The novel gene D2-2 is overexpressed in fresh GBM tissue and cell lines and is highly expressed in recurrent tumor tissue.148 No known sequence homology has been determined for this gene yet it functions during fetal development where it is expressed about 28-fold higher than in normal adult brains.149
The list of genetic lesions associated with the different grades of gliomas continues to increase. Several investigators have suggested that multiple pathways lead to the formation of GBMs.181 They concluded that GBMs could be distinguished on the basis of genetic defects even though they are histopathologically indistinguishable from other gliomas.
One pathway is the progressive stepwise evolution from a low grade to the more malignant anaplastic astrocytoma and finally to the GBM. The mutations associated with this pathway would include allelic loss of 17p or TP53 mutations and PDGF activation, allelic loss on 22q (astrocytoma), followed by allelic loss of 13q, 9p and 19q (anaplastic astrocytoma) to the GBM (Fig. 1). Gliomas that exhibit these aberrant characteristics seldom have EGFR amplification or loss of chromosome 10.181 This progressive pathway creates what some investigators call secondary or type 1 GBMs.185 Patients diagnosed with this progressive tumor tend to be young (mean age, 39 years) and to have had a less malignant tumor at the time of their original diagnosis.
In contrast, the second pathway represents GBMs that arise de novo or very rapidly from a pre-existing tumor. EGFR amplification and allelic loss on chromosome 10 are the hallmarks of this pathway (Fig. 1).110,173 These tumors are usually associated with older patients (mean age, 55 years) with no history of a lower grade tumor. These tumors are considered primary or type 2 GBMs.185 In addition to EGFR and allelic loss on chromosome 10, the MDM2 gene product also appears to be restricted to the primary de novo pathway.126 A third pathway is defined by the absence of either 17p allelic loss or TP53 mutations or EGFR amplification.181
Although additional data are needed to elucidate these pathways, genetic markers may be able to distinguish these subsets. For example, data strongly support that GBMs that have progressed from lower grade tumors have a high percentage of TP53 mutations (67%) and a low frequency or absence of EGFR amplification.129,185 These pathways may also be associated with gender differences181,185 and may respond differently to specific therapies.193 Investigations are underway to determine if the genetic lesions identified in these subsets of gliomas have prognostic significance.21
Pilocytic astrocytomas tend to occur in children and young adults and show no clear sex preference. These tumors arise throughout the CNS43 but have a predilection for the cerebellum and region of the third ventricle, the optic nerves, and the thalamus. Juvenile pilocytic astrocytomas are more common than either protoplasmic or gemistocytic astrocytomas and are remarkable for maintaining their low-grade status for long periods. They rarely demonstrate progressive behavior.
Pilocytic tumors have not been analyzed in great detail because most of these tumors are biopsied. Of the 49 cases of pilocytic astrocytomas reported in the cytogenetic literature,153 all but five occurred in children under the age of 19 years. Of these 49 cases, 31 contained no detectable chromosome abnormalities. In the cases with abnormal chromosomes, the most common finding was the gain of chromosome 7 (5 of 44 cases). Two additional cases had a structural rearrangement of chromosome 7.
Molecular analyses of pilocytic tumors have focused on the TP53 gene.62,153 Of 125 tumors analyzed, 18 contained a loss of 17p. The loss of heterozygosity, however, was not within the TP53 gene. The most common loss appeared to be in the telomeric region (17p13.3) of chromosome 17194 or in the 17q arm,176 where the NF-1 gene (17q11.2) is located. The allelic loss detected on chromosome 17q is of interest because pilocytic astrocytomas are often associated with neurofibromatosis type 1.43 Based on these limited data, a gene or genes other than the TP53 gene appear to be the targeted genetic loss in pilocytic astrocytomas. Other molecular studies include analyses of chromosomes 1p,9 1q,9 9p,2,6,42 10,97 11p,120 12q,127 and 22q,186 but each study included only a small number of cases. Additional material must be analyzed before the role of specific genes associated with pilocytic astrocytomas can be determined.
These tumors represent about 1% of the astrocytic neoplasms and typically develop in children and young adults without a sex bias.140 Cytogenetic studies performed on untreated tissue have reported numerical and structural abnormalities, but no consistent abnormality has been detected.153 Molecular studies of a small number of tumors have reported mutations in TP53, but no other allelic loss was identified.98,111
Giant Cell Glioblastomas
Also known as tuberous sclerosis, giant cell glioblastomas are a histological variant of GBMs. They account for less than 5% of the grade IV tumors, and their incidence peaks in the middle of the fifth decade.140 The giant cells within the tumor are the hallmark of this neoplasm. Two molecular investigations have identified TP53 mutations in more than 75% of the tumors analyzed.95,113 These same reports have also indicated that this group of tumors lacks other genetic alterations often associated with GBMs, such as EGFR, CDK4, and CDKN2 (MTS1/p16). The tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disease characterized by the development of benign tumors and hamartomas. Among other problems, these patients also develop subependymal giant-cell astrocytomas.140 One study of astrocytomas and ependymomas has reported a reduced expression of tuberin, the protein product of the TSC complex. The protein product was completely absent in the one giant cell glioblastoma that has been analyzed.192
Historically, the term ependymoblastoma referred to anaplastic ependymomas. Now, however, the term connotes embryonal tumors. Ependymomas develop from the ciliated epithelium that lines the ventricles of the brain and spinal canal. Embryologically, this cell layer is related to glia. When ependymal cells become transformed, they frequently express this glial heritage by acquiring a more astrocytic morphology. Ependymomas are most common during the first two decades of life,140 and their incidence is slightly higher for males than it is for females. They are more clearly defined from surrounding brain than other gliomas, although ependymomas demonstrate a spectrum of anaplasia. As with astrocytic tumors, histologic grade and survival do not appear to be correlated.
Summarizing the cytogenetic studies reviewed elsewhere,153 the most frequent abnormality is the loss of whole chromosome 22 in about 30% of the cases. Chromosome 22q is also involved in a number of structural rearrangements with most of the breakpoints localized to 22q12.153 The association between the loss of chromosome 22 and the location of the merlin gene at 22q12 is of interest. Patients with neurofibromatosis type 2 (NF-2) have a mutation in the merlin gene. They also have an increased incidence of intramedullary spinal ependymomas although intracranial ependymomas are rare.46 Abnormalities affecting the gain of chromosome 7 and the loss of 9p found so commonly in astrocytomas are not observed in ependymomas. Although far fewer ependymomas have been analyzed than astrocytomas, the former tend to lose chromosome 13q, the chromosome that contains the tumor suppressor gene, RB.62
Although a patient with a TP53 germ line mutation (Li-Fraumeni syndrome) has been reported to have developed intracranial ependymoma,94 molecular studies have rarely identified mutations of TP53.33,106,107,165 Another tumor suppressor gene may reside on 17p. One investigation reported that 50% of pediatric tumors had allelic loss on 17p, but the loss was distal to the TP53 gene. This allelic loss is similar to that identified in medulloblastomas.146 Genes associated with the cell cycle have also been found to be normal in ependymomas,142 and there is no evidence of EGFR amplification.11
This evidence confirms that the genetic lesions in astrocytomas are rare in ependymomas. These two types of brain tumors may therefore have different evolutionary pathways. Investigations of chromosome 22 suggest that a potential tumor suppressor gene resides there. A likely candidate gene is NF-2. One report detected mutations in the NF-2 gene,138 but other more extensive studies have failed to confirm this finding.11,54,138,158,182 Thus, more studies are needed to detect and clarify potential steps in the evolution of ependymomas.
Choroid Plexus Papillomas
This rare neoplasm most often occurs during the first decade of life and only rarely in adults. This tumor mimics its parental tissue by secreting cerebrospinal fluid and is one reason that hydrocephalus develops. The cells of the tumor appear strikingly normal and essentially free of mitotic activity. Only the crowding of cells identifies its neoplastic component. The number of cases reporting cytogenetic and molecular studies is limited. Half of the reported cases have normal karyotypes and the other half have numerical and structural abnormalities.153 Although choroid plexus papillomas have been identified in families with Li-Fraumeni syndrome,70 no other informative molecular studies have been performed.Figure 5. Chart illustrating normal brain tumor progression in oligodendrogliomas and oligoastrocytomas and known genetic lesions associated with specific tumor grades. In the oligoastrocytoma (mixed tumor), no specific genetic lesions have been identified.
Oligodendrogliomas and Mixed Tumors
These tumors occur primarily in adults with a peak incidence in the fifth and sixth decades of life.140 Children can also develop oligodendrogliomas. The mean age of pediatric patients with supratentorial tumors is 10 years and 7.5 years for those with infratentorial tumors.164 Oligodendrogliomas account for 10% of the gliomas diagnosed and are usually considered slow growing.140The location of oligodendrogliomas is roughly related to the amount of white matter in the different lobes of the brain. Although these tumors arise in white matter, they tend to infiltrate the cerebral cortex more than astrocytomas of similar grade. Histologically, oligodendroglial tumors comprise a continuous spectrum that ranges from very well-differentiated neoplasms to malignant invasive tumors. Similar features (i.e., high cell density, mitotic activity and necrosis) are used to grade oligodendrogliomas. How these markers correlate with survival is controversial. With increasing anaplasia, oligodendrogliomas begin to appear more astrocytic, and they can develop areas of necrosis.
As primary untreated tumors, oligodendrogliomas often have normal G-banded karyotypes. The single sex chromosome is lost in about 25% of the cases, and chromosome 7 is gained in about 5% of the cases. Structural abnormalities are rare, although several have been localized to chromosome 1p and chromosome 22q. These findings are reviewed elsewhere.153
Molecular analyses have been informative in defining the genetic lesions associated with this tumor (Fig. 5). Allelic loss on chromosomes 1p and 19q120,121 appears to be preferential for oligodendrogliomas.7,128,178,197 The most frequent allelic loss, which occurs on chromosome 19q, has been observed in 50 to 80% of the tumors analyzed4,8,75,178 despite the lack of cytogenetic evidence of numerical or structural abnormalities of this chromosome.153
A putative tumor suppressor gene has been mapped to 19q13.2-q13.3.139,197 Many genes known to be lost or mutated in tumors reside on chromosome 19q, (e.g., DNA repair genes, ERCC1, ERCC2, XRCC, and DNA ligase, cell cycle gene, BAX, and TGF-b1).96A protein serine-threonine phosphatase is being evaluated as the potential tumor suppressor gene.198 Chromosome 1p allelic loss has been identified in 40% to 97% of the tumors. These disparate results frequently reflect different probes or methods of analysis.9,75,128Typically, tumors carrying 1p deletions also carry 19q allelic loss.8,75,128
The location of a potential tumor suppressor gene(s) is not well defined for chromosome 1p. Two potential sites have been localized: one at 1p35-p36 and a second site closer to the centromere.7 Other allelic losses have been reported for chromosomes 4q, 11p and 22q but await additional studies to determine their relative importance.128,187 Occasionally, oligodendrogliomas have mutations in the TP53 gene but far less frequently than observed in astrocytic tumors.88,107,129 Allelic loss or mutations of TP53 occur in less than 15% of the oligodendrogliomas.88,107,128,129 Immunoreactivity, however, has been identified in a much higher percentage,76,112 and these differences are yet to be resolved.
Although these tumors are considered slow growing, many develop anaplasia in the form of increased cellularity, nuclear atypia, cellular pleomorphism, and high levels of mitotic activity. The anaplasia can be accompanied by angiogenesis and the proliferation of vessels and necrosis. The genetic lesions associated with these histological changes are not well defined for anaplastic oligodendrogliomas. Nonrandom allelic loss on chromosomes 9p and 10q is a possibility.128,196 A potential target gene on 9p21 is the cell-cycle inhibitor, CDKN2A (MTS1/p16). However, one report found no allelic loss or mutations in the CDKN2A gene.142 There is also no evidence that the recently cloned PTEN/MMAC-1 tumor suppressor gene on 10q23 is the target of the 10q loss observed in oligodendrogliomas.80,162 Isolated reports suggest that one of several other genes is co-amplified80,162 with EGFR amplification.
Interpreting these studies and the genetic lesions identified in grade III oligodendrogliomas is difficult because most of these tumors have been treated with radiation, chemotherapy, or both. It is unclear whether the changes are a response to treatment or whether they were already present and selected as the resistant cell surviving treatment. Additional studies are needed to clarify these issues.
Mixed tumors are composed of mixtures of oligodendroglial and astrocytic cells. The proportion of cells in this mixture varies considerably and is therefore a frequent point of contention among neuropathologists. The combination of glial cells most often observed in a mixed tumor is fibrillary astrocytes and oligodendrocytes. Mixtures of astrocytes and ependymal cells can occur but are thought to be rare. Such mixtures are also difficult to separate from ependymal tumors that have begun to acquire astrocytic phenotypes as discussed above. The cytogenetic literature has described 21 cases of mixed glioma, which are reviewed elsewhere.153 Summarized, however, the pattern of gain and loss in oligoastrocytomas is similar to that of oligodendrogliomas but without an astrocytic component. Again, more tumors must be analyzed to determine the presence of a nonrandom event.
Molecular studies have also been unable to identify a consistent genetic lesion that would indicate oligoastrocytomas are genetically distinct from either oligodendrogliomas or astrocytomas.128 A microdissection study of three different tumors determined that the different cellular components carried the same genetic lesions.75 About 30% of oligoastrocytomas carry genetic lesions often found in astrocytic gliomas, especially TP53 mutations and loss of heterozygosity on 17p.88,128 Furthermore, oligoastrocytomas with 17p loss or TP53 mutations show no allelic loss on 1p and 19q and vice versa. An extensive comparison of allelic loss in astrocytic tumors and oligodendrogliomas for chromosomes 1p, 17p and 19q suggested that mixed tumors have two genetic subsets—one genetically related to astrocytomas and the other to oligodendrogliomas.129
When mixed tumors acquire anaplastic features, they are also thought to acquire changes in 9p, 10, and 11p with occasional amplification of the EGFR gene or changes similar to the progressive changes of the anaplastic oligodendroglioma and astrocytoma.128 Again, more cases are needed for analysis before these patterns can be confirmed.
Brain Tumors from Mesenchymal Tissues
Gliosarcomas are thought to originate when gliomas generate reactive responses that cause vascular cells, vascular adventitia, and fibroblasts of the meninges to undergo cell division. In most instances this proliferation is benign. Occasionally, however, these processes become transformed and create a neoplasm containing transformed cells of glial and mesenchymal origins.
Gliosarcomas are very difficult to analyze cytogenetically unless tumor cells can be cloned directly from a freshly resected tumor. Without cloning, neither morphology nor intermediate filament staining can determine if a clonal abnormality derives from the glial or sarcomatous components. However, once a clonal cytogenetic abnormality has been established, fluorescent in situ hybridization could be used with paraffin-embedded tissue from the same patient to determine with which component the abnormality was associated.
Of six cytogenetic analyses of gliosarcomas in patients between 33 and 80 years old, four cases gained chromosome 7 while three cases lost chromosome 10. Structural abnormalities were common, but chromosome 9 was involved most frequently (five cases). Three cases had a translocation involving chromosome 9, but the breakpoints were different in each case. Molecular analyses of fresh tumor tissue are notably absent although occasional allelic loss and mutations of the TP53 gene have been detected.35,78
No single meningeal layer has been identified as the tumor-forming component of meningiomas. The incidence of these tumors is about 15% of all primary brain tumors.140 They can occur almost anywhere in the brain, but their greatest incidence is in the cerebral convexities and their lowest is in the pineal region. Although the overall incidence of spinal cord meningiomas is low, they still constitute the largest group of tumors in this region. Meningiomas develop in the middle decades of life and in the elderly, primarily in females (especially spinal meningiomas). They are rare in children, accounting for less than 2% of intracranial tumors.3 A familial occurrence, mostly associated with von Recklinghausens’s disease, is known. Most cases, however, are sporadic.
The current grading system recognizes three grades of meningiomas: benign (Grade I), atypical (Grade II), and anaplastic (Grade III). Benign tumors represent about 94% of the meningiomas; 5% are atypical and 1% are anaplastic.15,140 Atypical and anaplastic meningiomas pose the greatest risk of recurrence and therefore prognostic markers for those at risk would be helpful in determining the appropriate treatment for patients, especially children. Meningiomas have a wide range of histopathological appearances. The most common subtypes are meningothelial, fibrous, and transitional.140
Meningiomas were among the first solid tumors in which a nonrandom loss of a whole chromosome was identified.200 Monosomy 22 is the most consistent chromosomal aberration along with the deletion of chromosome 22.199 Despite its prevalence, this abnormality is independent of the tumor’s biological behavior. Tumor progression is thought to be more closely associated with the rearrangement or loss of chromosomes 1p, 14q, or both. The cytogenetic analysis of meningiomas is reviewed elsewhere.153 In general, molecular studies have reflected the chromosome abnormalities, especially for chromosome 22.25,26,82,92,141
Neurofibromatosis patients develop multiple meningiomas,137 and the NF-2 gene is localized to chromosome 22q12.136,166 Allelic loss on chromosome 22q and mutations in the NF-2 gene are observed in about 50 to 60% of the sporadic meningiomas25,26,141,150 and in meningiomas from patients with NF-2.150 This finding supports the hypothesis that the NF-2 locus encodes a tumor suppressor gene involved with meningiomas. In some studies mutations in NF-2 were as high as 70 to 80% when only fibroblastic and transitional meningiomas were included.189 In contrast, only 25% of the meningothelial meningiomas cases have contained an NF-2 mutation although this finding is controversial.47
Despite the association of meningiomas with NF-2 mutations, other sporadic patients and families with multiple meningiomas (familial) do not have a germ-line mutation in the NF-2 gene.117 Another locus on 22q may therefore encode a tumor suppressor gene. Allelic loss has been identified between 22q12.3 and the telomere, a region not associated with the NF-2 gene.133 Candidate genes under consideration are the
b-adaptin gene114 and MN1.79
Molecular studies that have detected allelic losses on chromosomes 1p5 and 14q93,157,167 support the cytogenetic data. However, additional allelic losses were detected for chromosomes 9q, 10q,82,131,157 and 17p.118,183 Each of these allelic losses occurs in tumors with more aggressive or invasive phenotypes.
Another phenotype beginning to emerge from the study of meningiomas is the aberrant expression of growth factors. In particular, the B chain of PDGF and the PDGF-b receptor have been identified.13,77,89,90 Their expression is suggestive of an autocrine mechanism. An immunohistochemical study further supports the possibility of an autocrine loop. Fresh meningioma tissue samples expressed the PDGF-B chain and PDGF-b receptor aberrantly, and this expression was localized to tumor tissue rather than to normal stroma.152Other growth factors identified in meningiomas include IGF-144,105,168 and TGF-b64,103 although their role in tumor progression awaits clarification.
Intracranial Schwann Cell Neoplasms
Schwannomas (neurilemmomas) are slow-growing, benign tumors that rarely undergo malignant changes. The most common Schwann cell neoplasm occurs on the eighth cranial nerve and less frequently on the fifth cranial nerve. Acoustic neuromas are derived from Schwann cells that envelop the vestibular branch of the 8th nerve. Most tumors are sporadic, but bilateral tumors are an indication of familial cases.140 Multiple peripheral schwannomas in the absence of neurofibromatosis features are characteristic of the newly described syndrome called schwannomatosis.87 The greatest incidence of this tumor is between the third and sixth decades of life with no sex predilection.
The NF-2 gene is considered the tumor suppressor gene responsible for the development of this neoplasm.57,58,151 The protein product of the NF-2 gene is called schwannomin/merlin, which is a member of a superfamily of proteins thought to play crucial roles in linking cell membrane proteins with the cytoskeleton.166 Cytogenetic20,132 and molecular studies have demonstrated that 40 to 60% of sporadic acoustic neurinomas have allelic loss on chromosome 22q.57,58,136,151,166 Immunohistochemical studies demonstrate the complete loss of schwannomin/merlin expression in schwannomas, further substantiating that eliminating the expression of schwannomin/merlin is an essential step in tumorigenesis.
At present no single chromosome abnormality clearly defines any one type or grade of brain tumor. The most common abnormality (the overrepresentation of chromosome 7) is present in about 60% of astrocytic tumors. It is unclear, however, if tumors lacking this abnormality represent a different subset of astrocytomas or whether it reflects a genetic instability that has by chance sorted human chromosomes in a way that provides a selective survival advantage to cells. When the changes in DNA have been assessed, patterns of change have been observed. Clearly, a series of step-wise activations and loss of genes occur during tumor progression, and these changes appear to be different types of brain tumors. Less clear is how tumors are initiated. Genetic changes in key genes such as TP53 are known to be early changes. Not all tumors, however, have an abnormality of this gene, suggesting that alternative pathways or mechanisms remain to be defined.
As new genetic abnormalities are defined, each has the potential to become a therapeutic target. Certainly, new drugs and gene therapy have expanded as such abnormalities have been defined. These new strategies differ from those of the past by specifically targeting tumor cells while sparing normal brain tissue.
Genetic lesions also offer the potential to be used as markers for diagnosis and prognosis, especially in genetic cancers like neuroblastomas. Such advances are in their infancy. This technology, however, has tremendous potential and will be part of the medical armament in the near future.
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