Toward a Survey of Somatic Mutation of the NF1 Gene in Benign Neurofibromas of Patients with Neurofibromatosis Type 1

Eisenbarth, Ingrid; Beyer, Kim S.; Krone, W.; Assum, Günter

doi:10.1086/302747

Cited by 81 publications

(73 citation statements)

References 25 publications

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“…Primer sequences for microsatellite markers were obtained from previously published studies (Eisenbarth et al, 2000) and from the genetic databases available online through the National Center for Biotechnology Information (NCBI) (http://www.ncbi.nlm.nih.gov). PCR amplification of microsatellite markers was performed as previously described (Lasota et al, 2001).…”

Section: Loh Studies Based On Pcr-amplified Microsatellite Markersmentioning

confidence: 99%

“…NF1 is mapped to the pericentromeric region of chromosome 17 (17q11.2) and encodes for a protein called "neurofibromin" (Xu et al, 1990a). Loss of heterozygosity (LOH) at the NF1 locus and inactivating mutations in the NF1 gene have been shown in NF1-associated and sporadic malignancies including neurofibromas, plexiform neurofibromas, malignant peripheral nerve sheath tumors, pilocytic astrocytomas, and desmoplastic/neurotropic melanomas (Colman et al, 1995;Däschner et al, 1997;Eisenbarth et al, 2000;Gutzmer et al, 2000;John et al, 2000;Kluwe et al, 1999Kluwe et al, , 2001Lothe et al, 1995;Perry et al, 2001;Serra et al, 1997;Skuse et al, 1989).Although the first report defining morphologic and immunohistochemical features of GI schwannomas dates back to the 1980s (Daimaru et al, 1988), there are no genetic studies regarding these tumors. The purpose of this study was to analyze 20 GI schwannomas for alterations of NF2 and NF1 tumor suppressor genes.…”

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confidence: 99%

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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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Section: Loh Studies Based On Pcr-amplified Microsatellite Markersmentioning

confidence: 99%

mentioning

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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“…According to the size of the shortened peptides the mutation was suspected within the second half of the analysed fragment. Therefore, a RT ± PCR product of exons 15 ± 21 of the NF1 gene was generated from RNA of the patient using the sense primer P7 14 and the antisense primer of fragment S2. The PCR product was cloned into an ATcloning vector and individual clones were subjected to sequence analysis.…”

Section: Molecular Analysismentioning

confidence: 99%

A patient severely affected by spinal neurofibromas carries a recurrent splice site mutation in the NF1 gene

et al. 2002

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Spinal neurofibromas are found in up to 38% of NF1 patients. However, they cause clinical implications only in about 5% of the patients. In contrast, multiple symptomatic spinal neurofibromas are the main clinical finding in patients with familial spinal neurofibromatosis. Familial spinal neurofibromatosis has been considered to be a distinct clinical form of neurofibromatosis. Linkage analysis in two families and identification of a NF1 gene mutation in a third family strongly associate spinal neurofibromatosis with the NF1 gene. We describe a NF1 patient who satisfies the NIH diagnostic criteria and has severe spinal involvement with bilateral spinal root neurofibromas at every level. A recurrent splice site mutation (IVS19b-3C4G) was identified in the NF1 gene in the patient. We discuss the possibility that the clinical picture of this patient represents an additional example of spinal neurofibromatosis. By comparison of the clinical expression of NF1 in this patient and that in another patient with the identical mutation the hypothesis that spinal neurofibromatosis is associated with a particular mutation is highly unlikely. The involvement of other genes linked to the NF1 gene or modifying genes is currently the most likely explanation for the clinical phenotype of spinal neurofibromatosis.

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“…1 The NF1 gene on chromosome arm 17q is supposed to be a tumour suppressor gene, of which, according to Knudson's two-hit model for tumorigenesis, 2 both alleles have to be inactivated for tumour formation to occur. Indeed, inactivation of both NF1 alleles has been demonstrated in four dermal neurofibromas, 3,4 in three plexiform neurofibromas, [4][5][6] and in a neurofibrosarcoma, 7 a malignant peripheral nerve sheath tumour (MPNST) for which NF1 patients are at increased risk. However, mutation and/or deletion of the NF1 gene, the latter often detectable as loss of heterozygosity (LOH), have only been reported for a limited fraction of the analysed neurofibromas.…”

Section: Introductionmentioning

confidence: 99%

Microsatellite instability and promoter methylation as possible causes of NF1 gene inactivation in neurofibromas

et al. 2000

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Neurofibromatosis type 1 (NF1) is a frequent hereditary disorder. One of the characteristic features of this disease is the development of neurofibromas. Since the NF1 gene is supposed to be a tumour suppressor gene, these neurofibromas should develop upon inactivation of both NF1 alleles. So far, mutation and deletion have been found to be involved in NF1 gene inactivation. However, these inactivating mechanisms explain the development of only a limited fraction of analysed neurofibromas. In this study, we investigated microsatellite instability (MSI) and promoter methylation as potential contributors to NF1 gene inactivation. As site-specific methylation in the NF1 promoter inhibits binding of transcription factors Sp1 and CREB, we studied the methylation status of their binding sites in particular. We analysed 20 neurofibromas and three neurofibrosarcomas, but did not find evidence for microsatellite instability or NF1 promoter methylation in any of the tumours. Thus, our data suggest that both microsatellite instability and promoter methylation are unlikely to be the major causes of NF1 gene inactivation in these tumours.

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Toward a Survey of Somatic Mutation of the NF1 Gene in Benign Neurofibromas of Patients with Neurofibromatosis Type 1

Cited by 81 publications

References 25 publications

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

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

A patient severely affected by spinal neurofibromas carries a recurrent splice site mutation in the NF1 gene

Microsatellite instability and promoter methylation as possible causes of NF1 gene inactivation in neurofibromas

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