12-NF1 updated

12-NF1 updated - PERSPECTIVES OPINION Neurofibromatosis...

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© 2005 Nature Publishing Group OPINION Neurofibromatosis type 1 — a model for nervous system tumour formation? Joshua B. Rubin and David H. Gutmann and mast cells. Neurofibromas have been subdivided into discrete (dermal) neurofi- bromas, which are associated with a single peripheral nerve, and diffuse (plexiform) neurofibromas, which involve multiple nerve fascicles. Molecular analyses of neurofibro- mas have shown that only the Schwann cells in these tumours exhibit biallelic inactivation of the NF1 gene and complete loss of expres- sion of neurofibromin (the protein encoded by NF1 ; see below). The other cellular ele- ments are genetically heterozygous for an inactivating NF1 mutation and therefore maintain neurofibromin expression 3–5 . Cutaneous (dermal) neurofibromas typically arise during the second decade of life, are often associated with the onset of puberty, and continue to increase in num- ber and size throughout adulthood. One of the curious features of these neurofibromas is their growth pattern, which is character- ized by an initial period of growth, followed by clinical quiescence for years or decades. On the basis of this pattern, it has been hypothesized that the neoplastic cellular elements within the tumour might be pro- liferating in response to a limiting supply of mitogen. In addition, the presence of other cell types within the tumour indicates that these stromal elements might directly influ- ence neurofibroma formation and growth by providing crucial mitogenic signals to NF1 –/– Schwann cells. Most peripheral nerve sheath tumours in individuals with NF1 are benign tumours with no lifetime risk of malig- nant transformation. However, the other subtype of neurofibroma (plexiform neu- rofibroma) can develop into cancer (malig- nant peripheral nerve sheath tumour; MPNST) 6 . Plexiform neurofibromas are thought to represent congenital tumours. They are often detected at birth and seem to enlarge more rapidly during the first decade of life. These tumours are similar to the discrete (cutaneous) neurofibroma, but are more extensive and often involve spinal or cranial nerve roots rather than Abstract | Neurofibromatosis type 1 (NF1) is a common genetic condition in which affected individuals develop benign and malignant nervous system tumours. Genetically engineered mouse (GEM) models of these NF1-associated nervous system tumours recapitulate several of the unique clinical aspects of the disease. Moreover, these Nf1 GEM models allow for a direct examination of the earliest stages of tumour evolution, including the contributions that Nf1 +/– cellular elements and cooperating genetic changes make to facilitate the transition from the pre-neoplastic to the neoplastic state and, in some cases, to promote malignant progression. Tumour-predisposition syndromes provide
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This note was uploaded on 05/26/2011 for the course BIO 445 taught by Professor Staff during the Spring '11 term at UNC.

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12-NF1 updated - PERSPECTIVES OPINION Neurofibromatosis...

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