title: Methylation analysis of the neurofibromatosis type 1 (NF1) promoter in peripheral nerve sheath tumours.
abstract: Peripheral nerve sheath tumours are hallmarks of neurofibromatosis type 1 (NF1). Development of plexiform neurofibromas to malignant peripheral nerve sheath tumours (MPNST) is common. The NF1 gene promoter harbours a hypomethylated CpG island. Thus, methylation changes may be involved in the development of different types of neurofibromas and malignant transformation. We investigated NF1-associated dermal (n=9) and plexiform neurofibromas (n=7), MPNST (n=5) and non-NF1 leucocyte samples (n=20) for their methylation pattern by bisulphite genomic sequencing. We could not find global hypermethylation in the NF1 promoter in our series. Nevertheless, site-specific methylation, involving transcription factor binding sites for SP1, CRE (-10), and AP-2, was observed. One region of the 5'-UTR (untranslated region) overlapping with a putative AP-2 binding site was methylated at 30-100% in 4/20 control samples. In conclusion, we did not find hypermethylation in NF1-associated tumours. Instead, low level methylation could parallel a global genomic hypomethylation in malignancy.
authors.affiliation: Institute of Neuropathology, Charité-University Medicine Berlin, Augustenburger Platz 1, Berlin 13353, Germany. anja.harder@charite.de
authors.forename: A
authors.initials: A
authors.lastname: Harder
authors.forename: M
authors.initials: M
authors.lastname: Rosche
authors.forename: D E
authors.initials: DE
authors.lastname: Reuss
authors.forename: N
authors.initials: N
authors.lastname: Holtkamp
authors.forename: K
authors.initials: K
authors.lastname: Uhlmann
authors.forename: R
authors.initials: R
authors.lastname: Friedrich
authors.forename: V F
authors.initials: VF
authors.lastname: Mautner
authors.forename: A
authors.initials: A
authors.lastname: von Deimling
mesh_terms: D000975:Antioxidants / Q000378:metabolism; D002999:Clone Cells; D019175:DNA Methylation; D004273:DNA, Neoplasm / Q000378:metabolism; D005260:Female; D006801:Humans; D007962:Leukocytes / Q000378:metabolism; D019656:Loss of Heterozygosity; D008297:Male; D008969:Molecular Sequence Data; D018317:Nerve Sheath Neoplasms / Q000235:genetics / Q000378:metabolism*; D009456:Neurofibromatosis 1 / Q000235:genetics / Q000378:metabolism*; D016133:Polymerase Chain Reaction / Q000379:methods; D011401:Promoter Regions, Genetic / Q000235:genetics*; D013447:Sulfites / Q000378:metabolism; D014158:Transcription, Genetic
chemical_list: D000975:Antioxidants; D004273:DNA, Neoplasm; D013447:Sulfites; C009279:sodium bisulfite