Neurofibromatosis type 1 (NF1) is a common autosomal dominant disease with a wide variety of features which primarily involve neural crest-derived tissues. NF1 is characterized by abnormal cell proliferation, particularly evident in the formation of benign neurofibromas and malignant neurofibrosarcomas. Nearly all NF1 patients develop neurofibromas while 3-5% develop neurofibrosarcomas. Presently there are no known measures for the prevention of NF1 tumor development, and treatment of these tumors using standard therapies has not proven to be particularly effective. An understanding of the progression of normal cells to a benign tumoral state and ultimately to a malignant one is presently lacking and would be invaluable for the development of preventive strategies, diagnostic tools and therapeutic approaches.
Every cell in a typical NF1 patient carries a constitutional NF1 mutation. Somatic mutation of the remaining NF1 allele appears to be involved in the formation of NF1 neoplasia, although the exact role and frequency of somatic NF1 mutations in tumors is unclear. While inactivation of both NF1 alleles may be sufficient for benign tumor formation, there may be a cascade of genetic events which mediate tumor progression in NF1, similar to other hereditary tumor disorders. In keeping with this notion, there have been several reports implicating the TP53 gene in the development of neurofibrosarcomas.
This proposal is designed to investigate these tumor progression pathways in NF1. To accomplish this, we will examine a large set of NF1 tumors (both benign and malignant) to specifically search for abnormalities in NF1 and TP53, and to investigate the possible involvement of other tumor-related genes through genetic and immunocytochemical techniques. A related aim is to study the functional effect(s) of NF1 and TP53 inactivation in Schwann cells through the use of antisense inhibition technology. This approach may mimic the properties of tumorigenicity conferred by NF1 and TP53 mutations. The combined use of these complementary approaches will lead to a more comprehensive understanding of the pathogenesis of tumors in NF1.