Interestingly NF2 mutations and merlin inactivation also occur in spontaneous schwannomas and meningiomas, as well as other types of cancer including mesothelioma, glioma multiforme, breast, colorectal, skin, clear cell renal cell carcinoma, hepatic and prostate cancer.
Loss of the long arm of chromosome 22, which is usually associated with inactivation of the NF2 gene, is the most common genetic abnormality found in meningiomas.
Allelic loss on 22q also is characteristic for meningiomas, however most of these alterations are considered to be associated with mutations of the NF2 gene.
Mutations of the NF2 gene on chromosome 22q are thought to initiate tumorigenesis in nearly 50% of meningiomas, and 22q deletion is the earliest and most frequent large-scale chromosomal abnormality observed in these tumors.
In addition, in these tumors, NF2 expression was reduced by a factor of 10 (p < 0.001, unpaired t test) in those meningiomas with NF2 gene mutations suggesting decreased stability or impaired transcription of mutated NF2 mRNA.
Genetic alterations in grade I meningiomas include frequent deletions of chromosomal locus 22q12 and NF2 gene mutations and uncommon somatic SMARCB1 and SMARCE1gene mutations; In grade II meningiomas, chromosomal losses occur on 1p, 22q, 14q, 18q, 10, and 6q, and gains on 20q, 12q, 15q, 1q, 9q, and 17q; In grade III meningiomas, losses have been recognized on 6q, 10, and 14q and alterations of PTEN, CDKN2A and CDKN2B genes.
These results provide evidence that mutations in the NF2 gene play an important role in the development of sporadic meningiomas as well as indicating a different tumorigenesis of these meningioma variants.
However, cytogenetic and molecular investigations have failed to detect either aberrations of chromosome 22 or mutations in the NF2 gene in approximately 40% of all tumors, thus making it apparent that an alternative mechanism(s) is responsible for the development of a large fraction of meningiomas.
These results provide additional evidence that mutations in the NF2 gene play an important role in the development of sporadic meningiomas and schwannomas.
Our results support previous observations that schwannomas and meningiomas, and to a lesser degree, ependymomas, express a high incidence of NF2 gene deletion, which supports the hypothesis that NF2 gene plays an important role in their tumorigenesis.
Transfection of genetic constructs of common NF2 missense mutations into NF2 gene-deficient meningioma cell lines revealed that merlin loss of function is due to a reduction in mutant protein half-life and increased protein degradation.
Chromosome 22q carries the locus of a tumor suppressor gene, the neurofibromatosis 2 (NF2) gene, which has been shown to be lost or mutated in some NF2-related tumors, sporadic meningiomas, and vestibular schwannomas, as well as a few other tumors.
Deficiency of the tumour suppressor merlin leads to the development of schwannomas, meningiomas and ependymomas occurring spontaneously or as a part of the hereditary disease Neurofibromatosis type 2 (NF2).