Vestibular Schwannoma and the NF2 Gene
Rebecca L. Bamford
Development of the majority of human cancers can be traced to alterations
in the standard pool of genetic information. Such chance mutations at the
cellular level of an individual exhibit a dominant pattern of genetic transmission
in families when passed from parent to child. Specifically, this is true
of a rare cancer of the eighth cranial nerves known as vestibular schwannoma.
Vestibular schwannoma is characterized by the formation of encapsulated
tumors resembling bunches of grapes in the Schwann cells of the ears. Symptoms
produced by such tumor formation include dizziness, imbalance, nausea, impaired
speech and hearing, ringing in the ears, facial paralysis, and the possibility
of coma or death at extreme levels of progression of the disease.
Vestibular schwannoma has an annual incidence of about 1 in 100,000 people
(Moffat 383). They can occur as both sporadic (95%) and familial (5%) disorders
(Moffat 383). Sporadic forms of the disease arise from acquired mutations
in the nucleus of a single cell that multiply to result in tumor formation.
Such spontaneous mutation cannot be passed on to the next generation because
both copies of the gene are normal at birth as they are inherited from parents
unaffected by the disease. The genetic information of the affected cell
is changed in a process separate from gametogenesis. Familial forms of vestibular
schwannoma arise from a germline mutation that can be passed on to later
generations. Both sex cells and somatic cells contain the mutation, giving
familial forms of vestibular schwannoma an autosomally dominant mode of
inheritance. Because the trait is autosomally dominant, children have a
50% chance of inheriting the mutant allele from a parent affected by vestilbular
schwannoma. For example, a woman that knows that her mother and brother
have vestibular schwannoma can expect a 50% chance of developing nerve sheath
The onset of vestibular schwannoma also exhibits a phenomenon called genomic
imprinting. Here, the genes for vestibular schwannoma are "labeled"
(via methylation, for example) for greater expression of the genetic information
contributed by one parent. This over expression of genes is not discriminatory
and can include those that cause disease. Vestibular schwannoma has been
shown to be much more severe if it is inherited from the maternal gene pool.
Increased severity includes earlier onset of the disease, as well as more
abundant and more rapidly-growing tumors. Based on a family history of the
disease then, an individual should seek determination of their own health
status as early as possible in order to avoid the pending effects of vestibular
schwannoma later in life.
Development of familial vestibular schwannoma has been traced to abnormalities
involving the NF2 gene on chromosome 22. NF2 is a tumor suppressor gene
that, when its genetic code is disturbed, predisposes patients to the development
of schwannomas of the vestibular nerves. The exact function of the NF2 gene
is yet unknown, but it encodes a structural protein of 595-amino acids called
schwannomin. Schwannomin is involved in regulating the stability of the
plasma membrane as it connects to the cytoskeleton in Schwann cells. When
NF2 is changed, the interactive membrane/cytoskeleton physical properties
also change, and the cell is more easily deformed. This deformability leads
to accelerated tumorigenesis, as NF2 encoded schwannomin protein does not
function adequately and Schwann cells experience differentiation into tumorous
growths (Lutchman 2270). In a 1995 study by Lutchman and Rouleau, mouse
fibroblast cells transfected with mutated NF2 were shown to experience altered
shape because of consequent production of a mutant protein. This protein
was inactive, resulting in increased rate of growth and transformed morphology
of the cell, especially in the cytoskeleton and its connection to the plasma
membrane (Lutchman 2273).
Mutations in the NF2 gene on chromosome 22, then, can result in the tumor
formation of vestibular schwannoma. Mutations can be divided into 3 categories:
point mutations, deletions, and insertions. A 1994 Princeton study found
that most insertions and deletions at the NF2 site caused a frameshift mutation
that led to early termination of the reading frame in the 14-200bp area
of the mutation. Here, the tumors studied had a stop codon created in the
site of the mutation. In general, the mutations observed created large scale
alteration of the structure of the schwannomin protein encoded, and resulted
in inactivation of the NF2 tumor suppressor gene (Lekanne Deprez 1027).
The nature of the chromosome 22/NF2 gene mutation is therefore suspected
to be the major determinant of Schwann cell proliferation in tumorigenesis
In a clinical setting, tumors symptomatic of vestibular schwannoma can be
identified by magnetic resonance imaging (MRI). On a chromosomal level though,
conclusive detection of mutations in the NF2 region of chromosome 22 can
be accomplished through PCR testing. In this process, RNA samples are isolated
from vestibular schwannomas and the enzyme reverse-transcriptase is used
to amplify the coding region of the NF2. The PCR-amplified products are
then run across an agarose gel to identify varying lengths of RNA occurring
because of deletions and insertions in the gene fragment transcripts. Technicians
perform this test in order to find evidence in the genetic information gathered
congruent with the hypothesis that altered NF2 gene size is causal in vestibular
schwannoma (Lekanne Deprez 1024).
The functions of a cell are controlled by proteins, which are encoded by
our genes. Cancer evolution is a process resulting in uncontrolled cellular
growth and tumorigenesis, as a result of the inactivation of tumor suppressor
genes. NF2 gene inactivation is similarly linked to the tumor formation
characteristic of vestibular schwannoma. Whether sporadic or familial, DNA
from vestibular schwannomas demonstrate chromosome 22 abnormalities, the
latter only possessing the capability of transmission to generations to
come. Vestibular schwannomas grow slowly over a period of years in the eighth
cranial nerve. This cancer can become life threatening as these tumors continue
to grow and press on the brainstem. Detection of the NF2 mutation at an
early stage of development is highly important, if not for the sake of those
inflicted by vestibular schwannoma, then for the consideration of the children
that will also suffer from the disease in generations to come.
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