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The Role of Cumulative Genetic Defeats in NF1 Tumorigenesis

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Annual rept. 1 Oct 1999-30 Sep 2000

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The purpose of this work is to study the genetic basis of tumor pathogenesis in neurofibromatosis type 1 NF1 . This work is testing the two-hit hypothesis in NF1 tumors benign neurofibromas and MPNSTs, to assay for involvement of the TP53 gene in the various types of tumors, and to determine whether other loci contribute to the formation of NF1 tumors. A large set of human primary tumor samples has been collected, with development of cell culture models from these tumors. One accomplishment is discovery of very strong evidence that the two-hit mechanism operates in at least a large proportion of neurofibromas, and that there is a genetically abnormal Schwann cell clonal component in these tumors, amidst other cell types. The TP53 gene has been found to be implicated only in the malignant tumors. The NF2 gene has allelic loss in some MPNSTs and plexiform tumors, although other tumor suppressor loci studied so far do not show any allelic imbalance. Substantial data from broader surveys of other genes differential display, cDNA array are forthcoming. These data are all important in the development of rational therapies to prevent or halt progression of neurofibroma and MPNST growth.

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  • Biochemistry
  • Medicine and Medical Research

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