National Cancer Institute®
Last Modified: May 1, 2002
UI - 11898512
AU - Korf BR
TI - Diagnosis and management of neurofibromatosis type 1.
SO - Curr Neurol Neurosci Rep 2001 Mar;1(2):162-7
AD - Partners Center for Human Genetics, Harvard Medical School, 77 Avenue Louis Pasteur, Suite 642, Boston, MA 02115, USA. firstname.lastname@example.org
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder whose major feature is the occurrence of multiple neurofibromas, which are benign tumors of the nerve sheath. It affects an estimated one in 3000 to 4000 individuals. In addition to neurofibromas, there are many other clinical manifestations, including malignant tumors such as gliomas or malignant peripheral nerve sheath tumors, and nontumor effects such as skeletal dysplasia and learning disability. Diagnosis is established on the basis of clinical criteria. Molecular genetic testing is feasible, but the large size of the gene and wide range of pathogenic mutations have so far impeded the development of a clinical diagnostic test. Insights into pathogenesis have followed from identification of the NF1 gene and the development of animal models. The major function of the gene product appears to be regulation of the ras protein. Tumors are believed to arise by the loss of function of the NF1 protein, suggesting that NF1 behaves as a tumor suppressor gene. Heterozygous effects on some cell types are also likely, however. The role of ras in the pathogenesis of tumors in NF1 has suggested an approach to treatment using ras inhibitors, some of which are likely to begin in clinical trials in NF1 patients in the near future.
UI - 11929829
AU - Gutmann DH; Hedrick NM; Li J; Nagarajan R; Perry A; Watson MA
TI - Comparative gene expression profile analysis of neurofibromatosis 1-associated and sporadic pilocytic astrocytomas.
SO - Cancer Res 2002 Apr 1;62(7):2085-91
AD - Department of Neurology, Washington University School of Medicine, St. Louis, Missouri 63110, USA. email@example.com
Pilocytic astrocytomas (PAs) are WHO grade I brain tumors that do not typically progress to more malignant grades of astrocytoma. Whereas there have been significant advances in the molecular genetics of high-grade astrocytomas, relatively little is known about the genetic changes associated with PA formation. In an effort to better characterize these low-grade neoplasms, we compared the gene expression profiles of six sporadic and two neurofibromatosis 1-associated PAs with other tissues and cell lines of both astrocytic and oligodendroglial origin. Hierarchical cluster analysis of gene expression data clearly delineated PAs from low-grade oligodendrogliomas and normal white matter. The two NF1-associated tumors and one of the sporadic PAs displayed expression profiles that were more closely related to those of cultured normal human fetal astrocytes. However, PAs also expressed individual genes typically associated with oligodendroglial lineage (e.g., proteolipid protein and PMP-22). The expression patterns of specific genes (e.g., ApoD) were unique to PA tumors, whereas genetic changes characteristic of high-grade astrocytomas were not encountered. Differential expression of two transcripts, neural cellular adhesion molecule and connexin-43, was confirmed at the protein level, suggesting that these cell adhesion molecules might be particularly important in the molecular pathogenesis of these tumors. We conclude that PAs are genetically unique gliomas with gene expression profiles that resemble those of fetal astrocytes and, to a lesser extent, oligodendroglial precursors.
UI - 11952554
AU - Alpsoy E; Ciftcioglu MA; Keser I; De Villiers EM; Zouboulis CC
TI - Epidermodysplasia verruciformis associated with neurofibromatosis type 1: coincidental association or model for understanding the underlying mechanism of the disease?
SO - Br J Dermatol 2002 Mar;146(3):503-7
AD - Department of Dermatology, Akdeniz University School of Medicine, 07070 Antalya, Turkey. firstname.lastname@example.org
We describe a 25-year-old man with epidermodysplasia verruciformis (EV) associated with neurofibromatosis type 1 (NF1). The lesions, persisting for more than 15 years, consisted of widespread planar warts on the backs of the hands and wrists, and reddish-brown macules on the trunk, neck and face. During the last 5 years, our patient developed several epithelial tumours, namely solar keratoses, plaques of Bowen's disease and squamous cell carcinomas (SCCs). He also presented with NF1 lesions with neurofibromas, cafe-au-lait macules, axillary freckling and Lisch nodules. He had left tibial bowing. Polymerase chain reaction analysis of the skin lesions demonstrated the presence of human papillomavirus (HPV) 15 in a flat wart, HPV 20 in a plaque of Bowen's disease, and HPV 15 and HPV 20 in an SCC lesion. Both EV and NF1 show an inherited predisposition to malignancy but the molecular mechanism underlying tumour development is not fully understood. The appearance of both diseases in our patient may be a coincidental association but may also contribute to the identification of loci for susceptibility to NF1 and EV on chromosome 17.
UI - 11760389
AU - Ueki K; Sasaki T; Ishida T; Kirino T
TI - Spinal tanycytic ependymoma associated with neurofibromatosis type 2--case report.
SO - Neurol Med Chir (Tokyo) 2001 Oct;41(10):513-6
AD - Department of Neurosurgery, University of Tokyo Hospital, Tokyo.
An 18-year-old girl with a 5-year history of neurofibromatosis type 2, consisting of bilateral acoustic tumors and a meningioma at the planum sphenoidale, presented with an intramedullary mass at the T-1 level, and underwent total removal of the tumor. Histological examination showed that the tumor consisted of markedly elongated spindle-shaped cells, which were immunopositive for S-100 protein and glial fibrillary acidic protein. Ultrastructural examination showed microvilli-lined lumina and prominent intercellular junctions, which were characteristic ependymal features. These findings were compatible with the diagnosis of tanycytic ependymoma. This rare subtype of ependymoma appears to arise through inactivation of NF2, in addition to some typical ependymomas.
UI - 11891502
AU - Neumann HP; Hoegerle S; Manz T; Brenner K; Iliopoulos O
TI - How many pathways to pheochromocytoma?
SO - Semin Nephrol 2002 Mar;22(2):89-99
AD - Nephrology Section, Department of Medicine, Albert-Ludwigs University, Freiburg, Germany. email@example.com
Pheochromocytomas, like several other tumors, may be either sporadic or the manifestation of a familial cancer syndrome. Recently, major advances have occurred in both the understanding of diverse molecular mechanisms leading to pheochromocytoma and the diagnostic modalities available for detection of the disease. Familial pheochromocytoma may be a manifestation of multiple endocrine neoplasia type 2 (MEN-2), von Hippel-Lindau (VHL), or neurofibromatosis-1 (NF 1) disease. Tumor-suppressor genes responsible for the familial occurrence of extra-adrenal pheochromocytoma, called paraganglioma, have been identified. This wealth of genetic information, coupled with the availability of sensitive and specific biochemical tests as well as imaging studies, allows for genetic screening and early diagnosis of pheochromocytoma. In addition, genetic screening of relatives at risk is now feasible. In this article, we review recent clinical and molecular advances in our understanding of pheochromocytoma. Copyright 2002, Elsevier Science (USA). All rights reserved.
UI - 11827459
AU - Chang LS; Akhmametyeva EM; Wu Y; Zhu L; Welling DB
TI - Multiple transcription initiation sites, alternative splicing, and differential polyadenylation contribute to the complexity of human neurofibromatosis 2 transcripts.
SO - Genomics 2002 Jan;79(1):63-76
AD - Children's Research Institute, Children's Hospital, The Ohio State University College of Medicine and Public Health, Columbus, OH 43205, USA. firstname.lastname@example.org
Northern blot analysis has shown that the human neurofibromatosis type 2 (NF2) cDNA hybridizes to multiple RNA species. To examine whether these hybridizing RNA species represent NF2 transcripts, we cloned the complete NF2 cDNA by a combination of techniques: 5' and 3' rapid amplification of cDNA ends, RT-PCR, and searching and sequencing the NF2-related cDNA clones from the IMAGE consortium. We showed that human NF2 transcripts initiate at multiple positions. Analogous to those reported previously, NF2 transcripts undergo alternative splicing in the coding exons. We isolated eight alternatively spliced NF2 cDNA isoforms, including one that contains a new exon termed exon 2', which potentially could encode proteins of different sizes. We assembled the overlapping cDNA fragments, and the longest NF2 cDNA, containing all 17 exons, consists of 6067 nucleotides, which is consistent with the size of the major RNA species hybridized to the NF2 probe. The cDNA has a 425-nucleotide 5' untranslated region upstream from the ATG start codon, and a long 3' untranslated region of 3869 nucleotides. We also isolated two shorter NF2 cDNAs that were terminated by different polyadenylation signal sequences, which indicates that differential usage of multiple polyadenylation sites also contributes to the complexity of human NF2 transcripts. By reference to the transcription initiation site mapped, we analyzed the 5' flanking sequence of the human NF2 gene. Transient transfection analysis in human 293 kidney, SK-N-AS neuroblastoma, and NT2/D1 teratocarcinoma cells with NF2 promoter-luciferase chimeric constructs revealed a core promoter region extending 400 base pairs from the major transcription initiation site. Although multiple regions are required for full promoter activity, a site-directed mutagenesis experiment identified a GC-rich sequence (position -58 to -46), which could be bound by transcription factor Sp1, as a positive cis-acting regulatory element. Cotransfection studies in Drosophila melanogaster SL2 cells showed that Sp1 could activate the NF2 promoter through the GC-rich sequence.
UI - 11979381
AU - Lomas J; Bello MJ; Alonso ME; Gonzalez-Gomez P; Arjona D; Kusak ME; de
TI - Campos JM; Sarasa JL; Rey JA Loss of chromosome 22 and absence of NF2 gene mutation in a case of multiple meningiomas.
SO - Hum Pathol 2002 Mar;33(3):375-8
AD - Department C. Experimental (Laboratorio de Oncogenetica Molecular), Hospital Universitario La Paz, Madrid, Spain.
Multiple meningiomas are rare, and only 13 cases have been subjected to molecular genetic analysis to detect mutations of the tumor-suppressor gene neurofibromatosis type 2 (NF2) located on chromosome 22. Most of these cases display NF2 gene mutations parallel to loss of the chromosome 22 homolog, indicating that inactivation of this gene may represent an early event in the development of multiple meningiomas. We report a case of a 61-year-old woman who developed multiple (dorsal and intracranial) meningiomas. Cytogenetic and molecular genetic studies demonstrated the loss of a copy of chromosome 22 in the 5 meningiomas studied and the absence of NF2 gene mutations in 4 of those available for this molecular analysis. These findings, together with similar data from 2 previously reported cases, suggest the participation of a tumor-suppressor gene other than NF2 on chromosome 22 in the pathogenesis of a subgroup of multiple meningiomas. Copyright 2002, Elsevier Science (USA). All rights reserved.
UI - 12011146
AU - Mohyuddin A; Neary WJ; Wallace A; Wu CL; Purcell S; Reid H; Ramsden RT;
TI - Read A; Black G; Evans DG Molecular genetic analysis of the NF2 gene in young patients with unilateral vestibular schwannomas.
SO - J Med Genet 2002 May;39(5):315-22
AD - University Department of Medical Genetics and Regional Genetic Services, St Mary's Hospital, Hathersage Road, Manchester M13 OJH, UK. email@example.com
Neurofibromatosis type 2 (NF2) must be suspected in patients presenting with a unilateral vestibular schwannoma at a young age who are therefore at theoretical risk of developing bilateral disease. We identified 45 patients aged 30 years or less at the onset of symptoms of a unilateral vestibular schwannoma. Molecular genetic analysis of the NF2 gene was completed on peripheral blood samples in all 45 and on 28 tumour samples. No pathogenic NF2 mutations were identified in any of the blood samples. NF2 point mutations were identified in 21/28 (75%) tumour samples and loss of heterozygosity (LOH) in 21/28 (75%) tumour samples. Both mutational hits were identified in 18/28 (65%) tumour samples. In one multilobular tumour, one (presumably first hit) mutation was confirmed which was common to different foci of the tumour, while the second mutational event differed between foci. The molecular findings in this patient were consistent with somatic mosaicism for NF2 and the clinical diagnosis was confirmed with the presence of two meningiomas on a follow up MRI scan. A further patient developed a contralateral vestibular schwannoma on a follow up MRI scan in whom neither of the truncating mutations in the vestibular schwannoma were present in blood. It is important when counselling patients with unilateral vestibular schwannomas to identify (1) those at risk of bilateral disease, (2) those at risk of developing other tumours, and (3) other family members at risk of developing NF2. Comparing tumour and blood DNA cannot exclude mosaicism in the index case and cannot, therefore, be used to predict those at risk of developing further tumours. However, identification of both mutations or one mutation plus LOH in the tumour and exclusion of those mutations in the blood samples of the sibs or offspring of the affected case may be sufficient to render further screening unnecessary in these relatives.
UI - 11988578
AU - Zhu Y; Ghosh P; Charnay P; Burns DK; Parada LF
TI - Neurofibromas in NF1: Schwann cell origin and role of tumor environment.
SO - Science 2002 May 3;296(5569):920-2
AD - Center for Developmental Biology, Department of Pathology, University of Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas, TX 75390-9133, USA.
Neurofibromatosis type 1 (NF1) is one of the most prevalent dominantly inherited genetic diseases of the nervous system. NF1 encodes a tumor suppressor whose functional loss results in the development of benign neurofibromas that can progress to malignancy. Neurofibromas are complex tumors composed of axonal processes, Schwann cells, fibroblasts, perineurial cells, and mast cells. Through use of a conditional (cre/lox) allele, we show that loss of NF1 in the Schwann cell lineage is sufficient to generate tumors. In addition, complete NF1-mediated tumorigenicity requires both a loss of NF1 in cells destined to become neoplastic as well as heterozygosity in non-neoplastic cells. The requirement for a permissive haploinsufficient environment to allow tumorigenesis may have therapeutic implications for NF1 and other familial cancers.
UI - 11836557
AU - Hung G; Li X; Faudoa R; Xeu Z; Kluwe L; Rhim JS; Slattery W; Lim D
TI - Establishment and characterization of a schwannoma cell line from a patient with neurofibromatosis 2.
SO - Int J Oncol 2002 Mar;20(3):475-82
AD - Department of Cell and Molecular Biology, House Ear Institute, Los Angeles, CA 90057, USA. firstname.lastname@example.org
By using retroviral mediated gene transfer technique, a primary schwannoma culture from a 56-year-old Neurofibromatosis type 2 (NF2) patient was immortalized with HPV E6-E7 genes. This cell line, HEI193, has a unique splice site mutation of the NF2 gene. Both immunocytochemistry and molecular biology techniques were used to demonstrate that this cell line is of Schwann cell origin. Comparison of the primary tumor with HEI193 revealed the same NF2 mutation and an identical pattern of allele loss at multiple loci, indicating that the established cell line had maintained many of the properties of the original tumor. The immortalized cell line was non-tumorigenic in both severe combined immunodeficient (SCID) mice and nude mice, but has altered growth properties such as higher proliferation rate and independence of Schwann cell growth factors. To our knowledge, this is the first attempt to establish permanent cell lines from human NF2 patients. This Schwann tumor-derived cell line may provide a useful model system for the study of familial NF2 tumor pathogenesis, for elucidating NF2 functions and for testing new gene-based therapeutic approaches.
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