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Kufe DW, Pollock RE, Weichselbaum RR, et al., editors. Holland-Frei Cancer Medicine. 6th edition. Hamilton (ON): BC Decker; 2003.

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Holland-Frei Cancer Medicine. 6th edition.

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NF1 and NF2 Genes

, MD, PhD and , MD.

NF1 Gene

von Recklinghausen or type 1 neurofibromatosis (NF1) is a dominantly inherited syndrome with variable disease manifestations, but the consistent feature is that tissues derived from the neural crest are most commonly affected. In addition to the nearly uniform development of neurofibromas, NF1 patients are at elevated risk of developing pheochromocytomas, schwannomas, neurofibrosarcomas, and primary brain tumors.221–223 The NF1 gene was initially localized to the pericentromeric region of chromosome 17q by linkage analyses.224, 225 Subsequently, karyotype studies of two NF1 patients identified germ line chromosomal rearrangements involving band 17q11.226, 227 In further work, both patients were found to have genetic alterations of a localized region of band 17q11. Intensive positional cloning efforts in this chromosome region led to the identification of the NF1 gene in 1991.228–230 The NF1 gene is large, spanning roughly 350 kb of DNA, and it encodes a protein product with a molecular mass of about 300 kilodaltons (kDa).222, 223, 231 Although germ line mutations in the NF1 gene are believed to underlie the development of the associated disease features in all or very nearly all NF1 patients, specific germ line NF1 mutations have been identified in approximately one-half to two-thirds of NF1 patients.222, 223, 231, 232 Difficulties in identifying germ line mutations in the NF1 gene in the remaining NF1 patients may be a result of the inherent inefficiencies and insensitivity associated with mutation detection strategies in such a large gene.

In addition to germ line NF1 mutations in those patients with NF1, the NF1 gene is affected by somatic mutations in a fraction of colon cancers, melanomas, neuroblastomas, and bone marrow cells from patients with the myelodysplastic syndrome.223, 231, 233–235 Consistent with its presumed tumor-suppressor role, the mutations inactivate NF1. Studies of leukemias arising in pediatric neurofibromatosis patients provide the clearest evidence that both copies of the NF1 gene are inactivated during tumorigenesis,236 as predicted by the Knudson model. Like the RB1, p53, and APC genes, the NF1 gene is expressed ubiquitously. Thus, as for other inherited cancer syndromes, the basis for the tissue specificity of the malignant tumors seen in neurofibromatosis patients (predominantly neurofibrosarcomas, leukemias, and primary brain tumors) remains puzzling. The NF1 protein product, termed neurofibromin, is a cytoplasmic protein with high similarity to guanosine triphosphate (GTPase)-activating proteins (GAPs).223, 237–239 Perhaps the best studied GAP is Ras-GAP, which markedly enhances the GTPase activity of the wild-type K-Ras, H-Ras, and N-Ras proteins. Although the means through which NF1 defects alter cell growth is not well understood, it is likely that inactivation of neurofibromin function leads to alterations in signaling pathways regulated by small Ras-like G proteins. Interestingly, NF1 null mice do not develop neurofibromas, but NF1 null, p53 null mice do, implicating p53 loss as a necessary step in the pathogenesis of this disease.240, 241

NF2 Gene

Neurofibromatosis type 2 (NF2, also known as central neurofibromatosis) is an autosomal dominant disorder that is distinct from NF1 on both genetic and clinical grounds.223, 242, 243 A hallmark of NF2 is the occurrence of bilateral schwannomas that affect the vestibular branch of the eighth cranial nerve (acoustic neuromas). NF2 patients are also at elevated risk for meningiomas, spinal schwannomas, and ependymomas. The NF2 gene was mapped to chromosome 22q by a combination of linkage analyses and LOH studies,244–246 and cloned, in 1993, via positional cloning approaches.247, 248 Germ line mutations inactivating the NF2 gene were observed in those patients with NF2, and somatic NF2 mutations were also seen in a subset of sporadic (non-NF2-associated) schwannomas and meningiomas. Somatic NF2 mutations in most other tumor types appear to be infrequent. However, preliminary studies indicate that the NF2 gene may be frequently affected by somatic mutations in malignant mesotheliomas,249 despite this tumor type not being seen at increased frequency in patients with NF2.242 The NF2 gene encodes a protein with strong similarity to a cytoskeletal protein family thought to act as linker proteins between integral membrane proteins and scaffolding proteins of the filamentous submembrane lattice.248 Consequently, NF2 gene alterations might contribute to tumor development, at least in part, via effects on cell shape, cell-cell interactions, and/or cell movement. Mouse studies confirm the importance of NF2 in tumor development. Although NF2 null mice typically develop osteosarcomas and not schwannomas, recent studies that used a conditional NF2 inactivation system in mouse Schwann cells appear to recapitulate the disease phenotype seen in humans.250

By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2003, BC Decker Inc.
Bookshelf ID: NBK12681

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