NF2 gene in neurofibromatosis type 2 patients

Zucman‐Rossi, Jessica; Legoix, Patricia; Sarkissian, H. Der; Chéret, Geneviève; Sor, Frédéric; Bernardi, Alberto De; Cazes, Lucien; Giraud, Sophie; Ollagnon, Elisabeth; Lenoir, Gilbert; Thomas, Gilles

doi:10.1093/hmg/7.13.2095

Cited by 73 publications

(53 citation statements)

References 30 publications

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“…Of the 16 intragenic alterations not removing either the initiator codon or native stop, 12 would be predicted to produce in-frame deletions and four out-of-frame deletions. A total of 29 constitutional gene-or chromosome-level gross rearrangements have been reported in NF2 patients, including four ring chromosome 22 cases [Kehrer-Sawatzki et al, 1997;Tsilchorozidou et al, 2004]; two translocations [Tsilchorozidou et al, 2004], and 23 complete gene deletions Trofatter et al, 1993;Watson et al, 1993;Evans et al, 1998;Zucman-Rossi et al, 1998;Bruder et al, 2001;Wallace et al, 2004;Diaz de Stahl et al, 2005;Kluwe et al, 2005;Sestini et al, 2005]. Because a much smaller number of samples have been studied with these techniques than with those used to determine small intragenic changes, further work is needed to understand the full spectrum of rearrangements involving the NF2 locus.…”

Section: Mutations and Polymorphisms Nf2 Constitutional Alterationsmentioning

confidence: 99%

Mutational spectrum of theNF2gene: a meta-analysis of 12 years of research and diagnostic laboratory findings

et al. 2007

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The NF2 tumor suppressor gene on chromosome 22 is a member of the protein 4.1 family of cytoskeletal elements. A number of single- and multiple-tumor phenotypes have been linked to alterations of NF2 since its characterization in 1993. We present a meta-analysis of 967 constitutional and somatic NF2 alterations from 93 published reports, along with 59 additional unpublished events identified in our laboratory and 115 alterations identified in clinical samples submitted to the Massachusetts General Hospital (MGH) Neurogenetics DNA Diagnostic Laboratory. In total, these sources defined 1,070 small genetic changes detected primarily by exon scanning, 42 intragenic changes of one whole exon or larger, and 29 whole gene deletions and gross chromosomal rearrangements. Constitutional single-exon events (N=422) were significantly more likely to be nonsense or splice site changes than somatic events (N=533), which favored frameshift changes (chi(2) test; P<0.001). Somatic events also differed markedly between tumors of different pathology, most significantly in the tendency of somatic events in meningiomas to lie within the 5' FERM domain of the transcript (Fisher's exact test; P<0.01 in comparison to schwannomas) with a complete absence of mutations in exons 14 and 15. There was no statistically significant difference in mutation type or exon distribution between published constitutional events and those found by the clinical laboratory. Less than 10% of all published and unpublished small alterations are nontruncating (N=63) and these changes are clustered in exons 2 and 3, suggesting that this region may be especially crucial to tumor suppressor activity in the protein.

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Section: Mutations and Polymorphisms Nf2 Constitutional Alterationsmentioning

confidence: 99%

Mutational spectrum of theNF2gene: a meta-analysis of 12 years of research and diagnostic laboratory findings

et al. 2007

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“…8,9,21,22,33,36,43,50,58,61,62,70,71,77 Abnormalities of the NF2 gene are also found in malignant mesothelioma, tumors that are not typically associated with neurofibromatosis. 26, 67 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).…”

Section: Overviewmentioning

confidence: 99%

Role of the neurofibromatosis Type 2 gene in the development of tumors of the nervous system

Ruttledge¹,

Rouleau²

2005

FOC

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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.

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“…A majority of the mutations are nonsense, frameshift, or spliced donor site mutations, all of which result in a nonfunctional, trun- cated protein. More recently, it was found that large deletions in the NF2 may be present in NF2 patients, raising the frequency of detectable NF2 alterations in this population to 84% (Zucman-Rossi et al, 1998). Development of bilateral vestibular schwannomas is a typical feature of NF2.…”

Section: Nf2 and Nf1 Status In Conventional Schwannomasmentioning

confidence: 99%

Evaluation of NF2 and NF1 Tumor Suppressor Genes in Distinctive Gastrointestinal Nerve Sheath Tumors Traditionally Diagnosed as Benign Schwannomas: A Study of 20 Cases

Lasota

Wasąg

Dansonka-Mieszkowska

et al. 2003

Laboratory Investigation

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SUMMARY:A significant percentage of conventional schwannomas, whether sporadic or associated with neurofibromatosis 2 (NF2), show loss of heterozygosity (LOH) at NF2 and/or NF2 inactivating mutations. Similarly, a significant percentage of neurofibromas show LOH at NF1 and/or NF1 inactivating mutations. There are no molecular genetic data on gastrointestinal (GI) nerve sheath tumors traditionally diagnosed as benign schwannomas, rare neoplasms possibly derived from the schwannian elements dispersed between the smooth muscle fibers. In this study, we analyzed 1 esophageal, 16 gastric, 1 small intestinal, and 2 colonic tumors of such type. Histologically, all were spindle cell neoplasms positive for S-100 protein, vimentin, and glial fibrillary acidic protein, and negative for smooth muscle markers, KIT, CD34, neurofilament proteins, and HMB45. Focal or extensive lymphoid cuffs, often containing germinal centers, were present in most cases. None of the patients had NF2 or NF1. Chromosomes 22 and 17, particularly NF2 and NF1 loci, were analyzed for LOH in all GI tumors and for comparative purposes in 10 conventional schwannomas. LOH on 22q was seen in 40% of conventional schwannomas but in only 5% (1 of 20) of GI schwannomas. PCR amplification followed by direct sequencing of PCR products failed to identify mutations in NF2 coding sequences (exons 1-15) in 13 cases, including a case with LOH on 22q. Losses on 17q involving NF1 were seen in both GI and conventional schwannomas in 50% and 33% of analyzed tumors, respectively. LOH at NF1 might be one of the genetic features seen in peripheral nerve sheath tumors from different locations and should be interpreted with caution. However, lack of NF2 alterations strongly supports the hypothesis that GI schwannomas represent a morphologically and genetically distinct group of peripheral nerve sheath tumors that are different from conventional schwannomas. (Lab Invest 2003, 83:1361-1371. Distinctive benign nerve sheath tumors traditionally diagnosed as schwannomas have been documented in the gastrointestinal (GI) tract. Their most common location is the stomach, followed by the colon and the rectum. Occasionally, similar tumors have been reported in the small intestine and esophagus. GI schwannomas are cellular spindle cell tumors with a microtrabecular pattern and lack of nuclear palisading. Peripheral lymphoid foci, sometimes with germinal center formation, are a common histologic feature. The tumor cells are positive for S-100 protein and glial fibrillary acidic protein (GFAP) and negative for desmin and ␣-smooth muscle actin (SMA), unlike true leiomyomas, and negative for KIT (CD117) and CD34, unlike GI stromal tumors. All tumors with such phenotypic features reported thus far have followed a benign clinical course (Daimaru et al, 1988;Hirose et al, 1997;Miettinen et al, 2001;Prévot et al, 1999;Sarlomo-Rikala and Miettinen, 1995;Sasatomi et al, 2000;Skopelitou et al, 1998;Tomozawa et al, 1998;Yagihashi et al, 1997).Neurofibromatosis 2 (NF2) is an autosomal dominant diso...

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NF2 gene in neurofibromatosis type 2 patients

Cited by 73 publications

References 30 publications

Mutational spectrum of theNF2gene: a meta-analysis of 12 years of research and diagnostic laboratory findings

Mutational spectrum of theNF2gene: a meta-analysis of 12 years of research and diagnostic laboratory findings

Role of the neurofibromatosis Type 2 gene in the development of tumors of the nervous system

Evaluation of NF2 and NF1 Tumor Suppressor Genes in Distinctive Gastrointestinal Nerve Sheath Tumors Traditionally Diagnosed as Benign Schwannomas: A Study of 20 Cases

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