Hypermethylation of the neurofibromatosis type 1 (NF1) gene promoter is not a common event in the inactivation of the NF1 gene in NF1-specific tumours

Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder char acterised by cafe-au-lait spots, neurofibromas and iris hamartomas. Since t he NF1 gene product neurofibromin contains a GAP-related domain involved in the down-regulation of p21(ras) oncogene activity, the NF1 gene has come t o be regarded as a tumour-suppressor gene. One common mechanism of tumour-s uppressor gene inactivation during tumorigenesis is promoter hypermethylati on, this "epi-mutation" being functionally equivalent to a second-hit somat ic mutation. To assess the importance of promoter hypermethylation in NF1 g ene inactivation in NF1-related tumours, the methylation status of the NF1 promoter region was determined by bisulphite-modified genomic sequencing in NF1-specific tumours and peripheral blood lymphocytes (PBL) from both NF1 patients and normal controls. Tumour-specific CpG methylation of six distin ct CpG sites was identified at positions -609, -429, -406, -383, -331 and - 315 relative to the transcriptional start site. However, since all other Cp G sites were unmethylated in all tissues examined, it is unlikely that CpG hypermethylation within the NFI promoter represents a common mutational mec hanism leading to neurofibroma formation.