Identification of NF1 mutations in both alleles of a dermal neurofibroma

A hallmark clinical feature of neurofibromatosis 1 (NF1) is multiple dermal neurofibromas, benign tumours that typically appear in early adolescence and increase in numbers throughout life. The pathogenesis of these tumours is not known. One domain of the NF1 gene product, neurofibromin, stimulates the intrinsic GTPase of Ras, and inactivation of both NF1 alleles has been demonstrated in specific malignancies. These observations support the contention that the NF1 gene product is a tumour suppressor that is involved in the Ras signal transduction pathway. Even though accumulating evidence demonstrates that NF1 acts as a tumour suppressor in some cells, mutations have not been identified in both NF1 alleles in dermal neurofibromas. Using standard techniques to analyse DNA extracted from benign neurofibromas, numerous investigators failed to identify loss of heterozygosity (LOH) in multiple tumours. In contrast to these reports, Colman et al. demonstrated NF1 LOH of dermal neurofibromas derived from 2 of 5 NF1 patients, yet the constitutional NF1 mutations in these patients were not identified, and the extent of the somatic deletions beyond the NF1 locus were not established. In this study, we show that a dermal neurofibroma from an NF1 individual who has a constitutional deletion of the entire NF1 locus harbours a 4-bp deletion of NF1 exon 4b in the other allele. This is the first definitive identification of a somatic mutation which is limited to the NF1 locus in a benign neurofibroma from an NF1 individual in whom the constitutional NF1 mutation is known.