title: The heterogeneous nature of germline mutations in NF1 patients with malignant peripheral serve sheath tumours (MPNSTs).
abstract: Malignant peripheral nerve sheath tumours (MPNSTs) are a major cause of mortality in patients with neurofibromatosis 1 (NF1). We have analysed lymphocyte DNA samples from 30 NF1 patients with MPNSTs to determine their underlying constitutional NF1 gene mutations. Mutations were detected in 27/30 (90%) of these patients. NF1 mutations identified included nonsense, missense, frameshift, splice site mutation and single or multi-exonic deletions and with no obvious clustering of the mutations across the gene. Fourteen of the mutations represent novel gene changes. There did not appear to be any relationship between the mutation type and the level of clinical severity observed. Of the 20 patients with high grade MPNSTs, seven patients had small (<20 bp) and multi-exonic deletions and three had small insertions (<20 bp). Several studies have suggested that NF1 patients with a constitutional 1.5 Mb deletion of the NF1 gene have an increased risk of developing malignant peripheral nerve sheath tumours (MPNSTs). None of our patients had a 1.5 Mb deletion. Larger prospective studies are needed to ascertain whether there is a different spectrum of NF1 mutations in NF1 patients with high grade compared to low grade MPNSTs and of patients with the 1.5Mb deletion, in order to determine the true frequency of MPNST in this sub-group of NF1 patients.
authors.affiliation: Institute of Medical Genetics, Cardiff University, Cardiff, Wales, United Kingdom.
authors.forename: Meena
authors.initials: M
authors.lastname: Upadhyaya
authors.forename: Gill
authors.initials: G
authors.lastname: Spurlock
authors.forename: Elisa
authors.initials: E
authors.lastname: Majounie
authors.forename: Sian
authors.initials: S
authors.lastname: Griffiths
authors.forename: Natalie
authors.initials: N
authors.lastname: Forrester
authors.forename: Mike
authors.initials: M
authors.lastname: Baser
authors.forename: Susan M
authors.initials: SM
authors.lastname: Huson
authors.forename: D
authors.initials: D
authors.lastname: Gareth Evans
authors.forename: Rosalie
authors.initials: R
authors.lastname: Ferner
mesh_terms: D000293:Adolescent; D000328:Adult; D004252:DNA Mutational Analysis; D016514:Genes, Neurofibromatosis 1; D018740:Genetic Heterogeneity; D018095:Germ-Line Mutation; D006801:Humans; D008875:Middle Aged; D018317:Nerve Sheath Neoplasms / Q000235:genetics*; D009456:Neurofibromatosis 1 / Q000235:genetics* / Q000401:mortality / Q000473:pathology