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25% of all genetic diseases are diseases of the brain.
The genetic basis of at least 40 distinct neurological
diseases has already been identified.
Strong evidence now exists, that genetic factors play a role
in the causation of certain types of brain tumors. Abnormal genes in
several types of brain tumors have been identified.
The
genetics of various brain tumors is broadly discussed in this review.
Gliomas:
Most gliomas occur as sporadic, noninherited tumors. A predisposition to
develop gliomas is also associated with some hereditary illness,
including NF-1, tuberous sclerosis complex, Gardner's syndrome, Turcot's
syndrome, and Li-Fraumeni syndrome. Gliomas with no clear pattern of
inheritance have been reported in families without these factors. In one
study, 6.7% of the patients had a blood relative with a glial tumors. In
addition, patients from later generations develop tumors at a younger age
and have a higher mortality.
A number of studies, primarily from the work of Binger and colleagues,
have suggested that suggested that despite the heterogeneity observed
among gliobastoma karyotypes, several distinct abnormalities are
frequently detected;
- Losses of chromosome 10(in 60%) and 17
- Gains of chromosome 7(81%)
- Translocations and deletions of chromosomes 9p occur at a lower
frequency [20%]
- Losses of chromosome 22 and sex chromosome have also been
reported.
Non random structural breakpoints have also been identified on the short arm
(p) of chromosome 9 (9p) and the long arm of chromosome 19(19q), and LOH
(evidence for tumor suppressor genes) has been shown frequently on
chromosomes 13, 17, and 22. Certain abnormal karyotypes such as loss of
chromosome 10, seem to correlate with increasing malignancy. In contrast,
alterations of chromosomes 13, 17, and 22 are observed in gliomas of all
grades.
Tumor oncogenes:
An oncogene is defined as any gene that can participate in the transformation
of cells to a malignant state. Most protooncogenes encode components of
signal transduction pathways by which extracellular factors regulate cell
growth, differentiation and survival.
These oncogenes are in fact growth factors and growth factor receptors,
located at the cell membrane transducer molecules, in the cytoplasm and
factors that regulate transcription in the nucleus.
Cellular proto-oncogenes are present in the genome of every cell and can
be activated to initiate tumor genesis, or to modify (accelerate) the
ongoing malignant transformation of the cell.
Although the functions of the proteins encoded by the most
proto-oncogenes are not precisely known, biochemical activities of
several proto-oncogene products have been identified. Some of the gene
products are identical or related to, proteins, known to be important in
growth regulation.
N-myc, c-myc: The amplification of the n-myc gene in
neuroblastomas appears to correlate with the clinical stage of the tumor
and with the poor prognosis of the patients. Therefore it is tempting to
speculate that the n-myc protein is one of the essential products
necessary for the aberrant behavior of neuroblastoma cells.
Fos,src: In benign gliomas, the fos gene appears to be expressed
ubiquitously compared with the n-myc and c-myc. Its function is poorly
understood , however, it has been proposed that it enhances metastatic
ability and that it can prevent a cell from entering into a quiescent
state(GO). The precise role of src, which encodes a protein that is a
tyrosine and phospholipid kinase, has remained an enigma despite the fact
that it was one of the first oncogenes identified.
Erb B: The v-erb B is responsible for the carcinogenic properties
of the avian erythroblastosis virus and has a nucleotide base sequence
similar to the EFGR gene.
Neu: The human neu gene, called c-erb B2, maps to chromosome
17p11-q21. Amplification and / or over expression of this gene occurs in
20% of breast tumors, and ovarian cancers and with a lower frequency in
other tumor types ,c-erb B2 protein is normally expressed in some areas
of fetal and adult human brain.
Ras: The 4 ras genes, ki-ras. N – ras. R-ras and Ha – ras encode
proteins of 21 kilodaltons (p21 ras ) that act as transducers or
modulators of receptor mediated signals that indirectly control cell
proliferation . Mutations of the p21 ras protein by alteration of only
one amino acid has been noted in many human carcinomas. Variable oncogene
expression could possibly be normal for brain or represent genetic
evidence of tumor multi-focality or infiltration.
c-sis: Platelet derived growth factor is a potent mitogen encoded
by the oncogene sis.
ros: Ros was first identified in the avian sarcoma virusUR2 as a
truncated retroviral gene. Subsequent studies have identified its human
cellular counterpart, located on chromosome 6. Ros encodes a putative
transmembrane receptor with a tyrosine domain that is homologous to many
other tyrosine kinase oncogenes (eg.erb-B) and receptor (eg. EGFR) . It
has been suggested that elevated ros expression is probably not important
in the pathogenesis of gliomas, although the possibility of small clones
in the tumor in which ros is expressed in significant levels, but diluted
by the larger portion of non-ros or non-ros-expressing cells cannot be
ruled out.
Gli: Amplification of a gene called gli, since it was first found
in a glioma, has been reported frequently, although the function is not
known. The gene, located on the chromosome 12 (12q12-q14.3 ) , has been
found to be highly expressed and amplified (50- to 75-fold )in a human
malignant cell line. It does not appear to be related to any of the
previously described oncogenes, nor has it so far been shown to posses
any transforming property. Its role in tumorigenesis is therefore
unclear.
Abl: Is situated on chromosome 9q34, near the centeromere. A
rearranged abl gene has been discovered in a glioblastome multiforme cell
line. Various brain tumour cell lines have been examined for oncogene
activation or over-expression.
Multi drug resistant gene (MDR): A vincristine resistant human
glioma cell line showed a decreased intracellular accumulation of
vincristine mediated by an increase in efflux of the drug and a reversal
of vincristine resistance by calcium entry blockers and calmodium
inhibitors. Using specific DNA probes, MDRI mRNA was shown to be
over-expressed without an amplification of the MDRI gene in MD resistant
glioma cell lines as compared to MD sensitive glioma cell lines. It would
be reasonable to suggest that amplification of the MDRI may not be a sine
qua non for acquisition of MDR and that the MDRI mRNA level may be well
co-related with the extent of MDR.
Outside the domain of the proto-oncogenes, the growth factors and growth
factor-receptors have been implicated in the development and progression
of several tumors.
Growth factors:
Several growth factors or their receptors have been found to be
over-expressed in gliomas.
Epidermal growth factor (EGF) is a small polypeptide which
has about 50% amino acid homology with transforming growth factor alpha (
GF – alpha )
EGF receptor is a multifocal allosteric transmembrane protein with
an intra cellular binding site for EGF, and acts as a tyrosine kinas4.
The gene for the EGFR is localized on the short arm of chromosome 7,
within 7p11 – 13 , and is called erb – B1. This receptor has been found
to be over-expressed in 50% to 70% of glioblastoma mulitforme.
Transforming growth factor alpha resembles EGF and binds the
EGFR to stimulate tyrosine kinase activity?
Platelet derived growth factor (PDGF) in glioblastomas as
well as in meningiomas is reported. PDGF is encoded by the oncogene sis,
located on chromosome 22.
Basic fibroblast growth factor ( b FGF ) is known to exert a
trophic effect upon a variety of cells of neural origin and is prevalent
in neural tissue. Human glioma cell lines express both a FGF – like
activity and a bFGF binding receptor and proliferate in response to
exogenously applied bFGF. It has also been suggested that bFGF may promote
glial tumor growth by the stimulation of angiogenesis or
neovascularisation.
Tumor suppressor genes:
More recently, loss of genetics material in glioblastomas has been
identified on chromosome 17 and chromosome 10. In most instances, losses
on chromosome 17 have been associated with early events in astrocytoma
formation, whereas losses on chromosome 10 have been associated with
progression to a more malignant phenotype, glioblastoma multiforme. Both
of these probably precede the amplification at the EFGR locus on
chromosome 7. Losses of chromosome 10 in glioblastomas occur at even
higher frequencies than of chromosome 17 and do not occur in low grade
gliomas.
These findings suggest multiple progressive genetic events, a concept
which is consistent with clinical observations of histological
progression that is often seen in gliomas. It must be noted, however,
that most of the karyotypic data are derived from highly malignant cell
lines and not from low grade gliomas and that they do not necessarily reflect
primary casual events.
Neurofibromatosis type1 (von Recklinghausens disease) is
associated with gliomas in 10 % of cases. Linkage analysis of large
kindreds localized the NF 1 gene on the long arm of chromosome 17.
The p53 suppressor gene is the most frequently altered gene in
human cancer and is also found mutated in several types of brain tumors.
It is located on chromosome 17p13, contains 11 exons and its
corresponding protein is composed of 393 amino acids. The expression of
wild type p53 is able to suppresses the transformation of cells by other
oncogenes, to inhibit the growth of of malignant cells in vitro and to
suppress the tumorigenic phenotype of malignant cells. At least two
stages in the cell cycle are regulated in response to DNA damage, the
G1-S and the G2- M transitions. The mutant p53 proteins examined so far
have a much longer half-life than that of the wild type, resulting in
large amounts of the mutant proteins in the transformed cells and tumors.
All identified mutants lose the ability to bind p53 – binding sites and
accordingly cannot activate the expression of adjacent reporter genes. It
is clear that different biological and biochemical properties. Perhaps
cancer patients with different p 53 mutant alleles have different
prognoses.
Cells transformed by both mutant p53 and ras have been obtained in which
the amount of mutant p53 can be controlled by am inducible vector.
Turning off the synthesis of mutant p53 in these cells results in a
dramatic loss of their transformed phenotypes , and they regain a normal
morphology. Therefore , the ratio of mutant to wild type p53 in a cell
could be critical in regulating cell division. Evidence that p 53
mutations can confer a phenotype on and promote the growth of cells when
heterozygous rests solely on cell culture experiments, although it is
hinted by the high risk of cancer seen in members of Li-Fraumeni families
heterozygous for mutant p 53.
Medulloblastomas:
Cytogenic studies reveal a near-diploid chromosomal complement with structural
abnormalities of chromosomes 17 and 1, and occasional DMs. 50% of them
show loss of genetic information on the short arm of chromosome 17
associated with monosomy 17p and trisomy 17q. Trisomy 1q is also
frequent.
Occasional tumors have displayed gene amplification; c-myc is most
frequently amplified, but amplification of N-myc and erbB has also been
reported. In one study, over 50% of the samples has shown overexpression
of N-myc and they have poor prognosis. Expression of the MDR 1 gene may also
be associated with poor prognosis.
Meningiomas:
Chromosomal aberrations: Some evidence exists that patients
with NF-2 and other families without evidence of neurocutaneous syndrome
have a genetic predisposition for these tumors.
Cytogenic studies of such tumors usually reveal a near diploid
chromosomal content associated with loss of genetic information on the
long arm (q) of chromosome22(22q). In more than 50% of them there is
complete loss of chromosome (monosomy 22). the maternal chromosome 22 and
the paternal chromosome 22 are lost with equal frequency. non random
findings include structural rearrangements of chromosomes 1, 7, and Y.
Some cytogenic abnormalities seem to predict tumor behavior; those with
increased hypodiploidy seem more likely to be biologically aggressive, to
be located on the convexity, and to lose their female predilection. In
addition, marked hypodiploidy show a spontaneous rate of chromosomal
breakage and rearrangement of about 20% as compared with a rate of 2% for
normal fibroblasts.
Oncogene amplification is rare; but proto-oncogenes that encode for
growth factors such as basic fibroblast growth factor (bFGF),
platelet-derived growth factor(PDGF) B (c-sis), and insulin-like growth
factors (IGF I and II), and growth factor receptors such as EGFR
(c-erbB), transducer molecules (K-ras), or transcription factors (c-myc)
have inappropriately enhanced levels of expression.
Schwannomas:
Many are associated with NF-2, but most occur sporadically. Monosomy 22
is the most frequent cytogenetic abnormality. Some are associated with
losses and structural rearrangements of many other chromosomes 6 and 9,
and gains of chromosome 7.
The NF-2 gene (schwannoma gene) locus is at 22q12. This gene contains 17
exons and codes for a 69-kilodalton protein termed merlin, loss of which
is associated with tumorigenesis. lately, bFGF and a glial growth
factor-like substance have been implicated in these tumors.
Pituitary adenomas:
Some isolated familial clusters of pituitary adenomas have been reported.
Most hereditary forms occur in association with autosomal dominantly
inherited, multiple endocrine neoplasia, type I (MEN I). All first degree
relatives of such patients should undergo a screening.
The incidence of pituitary tumors, usually prolactinomas, in MEN I is
about 65% and they have a high rate of recurrence and warrant additional
therapy following surgery.
Cytogenic studies reveal occasional aneuploidy or hypodiploidy and
nonrandom chromosome abnormalities of chromosomes 1, 4, 7, and 19q. Biologically
aggressive and hormone secreting tumors have a higher incidence of
chromosomal abnormalities. Sporadic pituitary adenomas derive from the
monoclonal expansion of a single mutated cell. A subset of GH-producing
pituitary adenomas has been found to contain a somatic mutation of the
gsp oncogene. It has been suggested that autocrine mechanisms may also
play a role in these tumors.
Others:
Glomus (chemodectomas or paraganglioms) tumors tend to occur more
frequently in families and in multiple locations. They appear to be
inherited in an autosomal dominant fashion, transmitted almost
exclusively by males. Upto 30% of patients with a positive family history
will have a second paraganglioma.
Inherited DNA sequences in choroid plexus papillomas (because of its
association with Li-Fraumeni and Aicardi's syndromes), have been
suggested.
Conclusion:
Genetic studies have focused primarily on chromosomal aberrations, the
role of mitogenic/differentiation factors and their surface receptors,
proto-oncogenes, and, more recently, tumor suppressor genes. In the near
future, it is hoped, this explosion of genetic knowledge will lead to
newer rational therapies.
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