Lauren Fishbein | Search PubMed

PubMed2005

Analysis of somatic NF1 promoter methylation in plexiform neurofibromas and Schwann cells.

Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with the characteristic feature being the neurofibroma. It is believed that both NF1 alleles must be inactivated as the first step in tumorigenesis. However, often the somatic mutations are not identified, suggesting that epigenetic changes such as methylation could account for the "second hit" in some tumors. The literature reports that the region of the NF1 promoter surrounding the transcription start site is completely unmethylated in several normal tissues and some NF1-related dermal and plexiform neurofibromas. We analyzed the methylation state of the NF1 promoter in normal Schwann cells (the cell type clonally expanded in neurofibromas) and in NF1-related plexiform tumor samples with unidentified somatic mutations. In a region of 451 bp surrounding the transcription start site, a low level of methylation was found at several specific cytosines in 12 of 18 tumor samples. Overall, epigenetic silencing through methylation does not appear to be a major mechanism for the second hit. However, this study, which analyzed the largest number of NF1-related plexiform tumors and is the first to include Schwann cell-enriched tumor cultures, detected greater methylation than in any previous reports. This suggests that methylation, especially at potential transcription factor binding sites, is moderately perturbed in some plexiform neurofibromas and should be investigated further.

Cells, Cultured↗

PubMed2002

NF1 mutations and molecular testing.

Neurofibromatosis 1 is a progressive autosomal dominant condition caused by mutations in the NF1 gene on chromosome 17. The condition shows clinical variable expressivity, with varying features even between family members who share the same mutation. Furthermore, it is impossible to precisely predict the severity and course of the condition, a source of frustration for families and physicians. Neurofibromatosis 1 is also heterogeneous at the mutation level, with more than 300 independent mutations having been reported in this gene. The mutation data have accumulated slowly owing to the variability of the mutation types and the size and complexity of the gene. This is also reflected in the lack of a simple, inexpensive, highly accurate DNA-based test for neurofibromatosis 1 at present. This article reviews current NF1 mutation spectrum and testing, discussing and illustrating mutation mechanisms and pathogenetic effects, as well as factors affecting DNA testing and interpretation/diagnosis.

Child↗