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 tumors herself.

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 vestibular schwannoma.

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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