The Development of Tumors of the Nervous System
The Development of Tumors of the Nervous System
Germ line and somatic mutations in the neurofibromatosis Type 2 (NF2) tumor suppressor gene predispose individuals to tumors of the nervous system, including schwannomas and meningiomas. Since identification of the NF2 gene more than a decade ago, a large body of information has been collected on the nature and consequences of these alterations in patients with NF2 and in individuals in whom sporadic tumors associated with NF2 develop. The catalog of mutations identified thus far has facilitated extensive genetic analysis, including studies of patients with mosaicism and phenotype-genotype correlations, and has also led to experiments that have begun to unravel the molecular biology of the NF2 gene and its role in tumorigenesis. The authors describe some of the most significant findings in NF2 genetics and biology over the last decade.
The NF2 tumor suppressor gene, which is located on chromosome 22, was identified in 1993. The clinical syndrome NF2 (previously termed central neurofibromatosis or bilateral acoustic neurofibromatosis) had been described more than 170 years earlier. It became clear during the twentieth century (predominantly during the latter half) that NF2 was a distinct clinical entity from NF1 (von Recklinghausen disease or peripheral neurofibromatosis). The NF2 gene codes for a protein named separately by the two groups who identified it in 1993; that is, schwannomin or merlin. Schwannomin was proposed as a name for the NF2 gene because of its inactivation in schwannomas. Merlin was suggested because of the homology of the NF2 gene to the ERM family of proteins: moesin, ezrin, and radixin. Nevertheless, neither term has been universally accepted, and it would appear that a hybrid name is required. In an attempt to incorporate both names and to avoid further confusion in the literature, we suggest that the gene be referred to as schmerlin.
There have been numerous publications in which alterations in the NF2 gene have been described (both in patients with and without NF2), which predispose individuals to nervous system tumors, including schwannomas, meningiomas, and ependymomas. Abnormalities of the NF2 gene are also found in malignant mesothelioma, tumors that are not typically associated with neurofibromatosis. The presence of multiple meningiomas/schwannomas in an individual usually implies that there is a germ line mutation (with every cell in the body containing that mutation) or that the patient is a mosaic for a particular mutation (a proportion of cells within the individual's tissues harbor a mutation as a result of a postzygotic event). Clinically, these patients are deemed to have classic NF2. Mild cases of NF2 usually result from a particular type of mutation (see GenotypePhenotype Correlation in NF2), or may be the result of mosaicism (because the mutation is not present in every cell of the body). For obvious reasons, severe cases of NF2 are less likely to be the result of mosaicism.
Solitary meningiomas or schwannomas in an individual are normally the result of somatic mutation within the NF2 gene in a single cell of neural crest origin. A "second hit" to knock out the remaining copy of the NF2 locus is then required to give this cell a growth advantage, which eventually leads to tumorigenesis. This second hit often consists of loss of one entire copy of chromosome 22 or a large proportion of the chromosome. This is usually the result of nondisjunction during mitosis in the cells containing the original point mutation. The term "loss of heterozygosity" describes the experimental findings in tumors that are missing one copy of a particular chromosomal region. The "two hit" model of tumorigenesis involving tumor suppressor genes was first proposed by Knudson.
It is likely that mutations in other, as yet unknown genes are necessary before a schwannoma or meningioma develops. One such candidate is the P53 tumor suppressor gene, which has recently been shown to act synergistically with the NF2 gene (in conditional NF2 mutant mice) in the development of malignant tumors of neural crest origin. Furthermore, mutation/loss of the NF2 gene is probably an early event in tumor development, with aberrations of genes on other chromosomes resulting in a more aggressive phenotype.
Germ line and somatic mutations in the neurofibromatosis Type 2 (NF2) tumor suppressor gene predispose individuals to tumors of the nervous system, including schwannomas and meningiomas. Since identification of the NF2 gene more than a decade ago, a large body of information has been collected on the nature and consequences of these alterations in patients with NF2 and in individuals in whom sporadic tumors associated with NF2 develop. The catalog of mutations identified thus far has facilitated extensive genetic analysis, including studies of patients with mosaicism and phenotype-genotype correlations, and has also led to experiments that have begun to unravel the molecular biology of the NF2 gene and its role in tumorigenesis. The authors describe some of the most significant findings in NF2 genetics and biology over the last decade.
The NF2 tumor suppressor gene, which is located on chromosome 22, was identified in 1993. The clinical syndrome NF2 (previously termed central neurofibromatosis or bilateral acoustic neurofibromatosis) had been described more than 170 years earlier. It became clear during the twentieth century (predominantly during the latter half) that NF2 was a distinct clinical entity from NF1 (von Recklinghausen disease or peripheral neurofibromatosis). The NF2 gene codes for a protein named separately by the two groups who identified it in 1993; that is, schwannomin or merlin. Schwannomin was proposed as a name for the NF2 gene because of its inactivation in schwannomas. Merlin was suggested because of the homology of the NF2 gene to the ERM family of proteins: moesin, ezrin, and radixin. Nevertheless, neither term has been universally accepted, and it would appear that a hybrid name is required. In an attempt to incorporate both names and to avoid further confusion in the literature, we suggest that the gene be referred to as schmerlin.
There have been numerous publications in which alterations in the NF2 gene have been described (both in patients with and without NF2), which predispose individuals to nervous system tumors, including schwannomas, meningiomas, and ependymomas. Abnormalities of the NF2 gene are also found in malignant mesothelioma, tumors that are not typically associated with neurofibromatosis. The presence of multiple meningiomas/schwannomas in an individual usually implies that there is a germ line mutation (with every cell in the body containing that mutation) or that the patient is a mosaic for a particular mutation (a proportion of cells within the individual's tissues harbor a mutation as a result of a postzygotic event). Clinically, these patients are deemed to have classic NF2. Mild cases of NF2 usually result from a particular type of mutation (see GenotypePhenotype Correlation in NF2), or may be the result of mosaicism (because the mutation is not present in every cell of the body). For obvious reasons, severe cases of NF2 are less likely to be the result of mosaicism.
Solitary meningiomas or schwannomas in an individual are normally the result of somatic mutation within the NF2 gene in a single cell of neural crest origin. A "second hit" to knock out the remaining copy of the NF2 locus is then required to give this cell a growth advantage, which eventually leads to tumorigenesis. This second hit often consists of loss of one entire copy of chromosome 22 or a large proportion of the chromosome. This is usually the result of nondisjunction during mitosis in the cells containing the original point mutation. The term "loss of heterozygosity" describes the experimental findings in tumors that are missing one copy of a particular chromosomal region. The "two hit" model of tumorigenesis involving tumor suppressor genes was first proposed by Knudson.
It is likely that mutations in other, as yet unknown genes are necessary before a schwannoma or meningioma develops. One such candidate is the P53 tumor suppressor gene, which has recently been shown to act synergistically with the NF2 gene (in conditional NF2 mutant mice) in the development of malignant tumors of neural crest origin. Furthermore, mutation/loss of the NF2 gene is probably an early event in tumor development, with aberrations of genes on other chromosomes resulting in a more aggressive phenotype.