Toward a survey of somatic mutation of the NF1 gene in benign neurofibromas of patients with neurofibromatosis type 1

Neurofibromatosis type 1 (NF1), a common autosomal dominant disorder caused by mutations of the NF1 gene, is characterized by multiple neurofibromas, pigmentation anomalies, and a variety of other possible complications, incl uding an increased risk of malignant neoplasias. Tumorigenesis in NF1 is be lieved to follow the two-hit hypothesis postulated for tumor-suppressor gen es. Loss of heterozygosity (LOH) has been shown to occur in NF1-associated malignancies and in benign neurofibromas, but only few of the latter yielde d a positive result. Here we describe a systematic approach of searching fo r somatic inactivation of the NF1: gene in neurofibromas. In the course of these studies, two new intragenic polymorphisms of the NF1 gene, a tetranuc leotide repeat and a 21-bp duplication, could be identified. Three tumor-sp ecific point mutations and two LOH events were detected among seven neurofi bromas from four different NF1 patients. Our results suggest that small sub tle mutations occur with similar frequency to that of LOH in benign neurofi bromas and that somatic inactivation of the NF1 gene is a general event in these tumors. The spectrum of somatic mutations occurring in various tumors from individual NF1 patients may contribute to the understanding of variab le expressivity of the NF1 phenotype.