Title: Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas
Authors: Thomas, Laura ×
Spurlock, Gill
Eudall, Claire
Thomas, Nick S
Mort, Matthew
Hamby, Stephen E
Chuzhanova, Nadia
Brems, Hilde
Legius, Eric
Cooper, David N
Upadhyaya, Meena #
Issue Date: Apr-2012
Publisher: Karger
Series Title: European Journal of Human Genetics vol:20 issue:4 pages:411-419
Article number: 10.1038/ejhg.2011.207
Abstract: Neurofibromatosis type-1 (NF1), caused by heterozygous inactivation of the NF1 tumour suppressor gene, is associated with the development of benign and malignant peripheral nerve sheath tumours (MPNSTs). Although numerous germline NF1 mutations have been identified, relatively few somatic NF1 mutations have been described in neurofibromas. Here we have screened 109 cutaneous neurofibromas, excised from 46 unrelated NF1 patients, for somatic NF1 mutations. NF1 mutation screening (involving loss-of-heterozygosity (LOH) analysis, multiplex ligation-dependent probe amplification and DNA sequencing) identified 77 somatic NF1 point mutations, of which 53 were novel. LOH spanning the NF1 gene region was evident in 25 neurofibromas, but in contrast to previous data from MPNSTs, it was absent at the TP53, CDKN2A and RB1 gene loci. Analysis of DNA/RNA from neurofibroma-derived Schwann cell cultures revealed NF1 mutations in four tumours whose presence had been overlooked in the tumour DNA. Bioinformatics analysis suggested that four of seven novel somatic NF1 missense mutations (p.A330T, p.Q519P, p.A776T, p.S1463F) could be of functional/clinical significance. Functional analysis confirmed this prediction for p.S1463F, located within the GTPase-activating protein-related domain, as this mutation resulted in a 150-fold increase in activated GTP-bound Ras. Comparison of the relative frequencies of the different types of somatic NF1 mutation observed with those of their previously reported germline counterparts revealed significant (P=0.001) differences. Although non-identical somatic mutations involving either the same or adjacent nucleotides were identified in three pairs of tumours from the same patients (P<0.0002), no association was noted between the type of germline and somatic NF1 lesion within the same individual.European Journal of Human Genetics advance online publication, 23 November 2011; doi:10.1038/ejhg.2011.207.
ISSN: 1018-4813
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Department of Human Genetics - miscellaneous
Laboratory for Neurofibromatosis Research
× corresponding author
# (joint) last author

Files in This Item:
File Description Status SizeFormat
Thomas EJHG 2012.pdfpublisher's version pdf Published 466KbAdobe PDFView/Open Request a copy

These files are only available to some KU Leuven Association staff members


All items in Lirias are protected by copyright, with all rights reserved.

© Web of science