Neurofibromatosis type I (NFI) is a common autosomal dominant disorder with an increased risk for developing benign and malignant tumors. The NFI gene has been cloned and maps to 17q I I .2, and the gene product acts as a tumor suppressor gene. Here we analyzed the role of mutations in TP53 in four malignant NF I tumors. Mutations were found in 3 out of 4 tumors. One of these mutations is a common rnissense mutation in codon 278 in one of the previously identified hot spots for mutations. The two other are hitherto unreported mutations, including a splice mutation of exon 3 and a nonsense mutation in exon 4. In addition, these four tumors also showed loss of heterozygosity (LOH) for markers on chromosome 17 in the region of Tf53. Malignant NFI tumors are initiated by a somatic inactivation of the second NFI allele. Tumor progression, however, occurs by accumulation of additional genetic abnormalities, such as homozygous inactivation of TP53, as demonstrated in this paper. Genes Chrornosorn Concer /0:250-255 ( I 994). 0 I994 Wiley-Liss. Inc.
I N T R O D U C T I O N
Neurofibromatosis type I ( N F l ) , is a frequent autosomal dominant disorder in humans with an incidence of 1 in 3,000 (Crowe et al., 1956). T h e disease is characterized by cafe-au-lait spots, Lisch nodules, multiple neurofibromas, and learning disorders (Riccardi and Eichner, 1988). N F 1 can be classified as a hereditary cancer syndrome, because individuals with N F 1 are at increased risk for developing benign and malignant tumors, including optic gliomas and neurofi brosarcomas (Knudson,