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Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 ( NF1 ) gene in neurofibromatosis patients with benign and malignant tumors

2004; Wiley; Volume: 23; Issue: 2 Linguagem: Inglês

10.1002/humu.10305

1098-1004

Meena Upadhyaya, Song Han, Claudia Consoli, Elisa Majounie, Martin Horan, Nick Thomas, Christopher Potts, S. W. Griffiths, Martino Ruggieri, Andreas von Deimling, D.N. Cooper,

Sarcoma Diagnosis and Treatment

Human MutationVolume 23, Issue 2 p. 134-146 Research Article Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors† Meena Upadhyaya, Corresponding Author Meena Upadhyaya [email protected] Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKInstitute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UKSearch for more papers by this authorSong Han, Song Han Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorClaudia Consoli, Claudia Consoli Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorElisa Majounie, Elisa Majounie Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorMartin Horan, Martin Horan Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorNick S. Thomas, Nick S. Thomas Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorChristopher Potts, Christopher Potts Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorSian Griffiths, Sian Griffiths Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorMartino Ruggieri, Martino Ruggieri Institute of Bioimaging and Pathology of the Central Nervous System, National Research Council, Catania, ItalySearch for more papers by this authorAndreas von Deimling, Andreas von Deimling Institut für Neuropathologie, Charité, Humboldt-Universität, Berlin, GermanySearch for more papers by this authorDavid N. Cooper, David N. Cooper Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this author Meena Upadhyaya, Corresponding Author Meena Upadhyaya [email protected] Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKInstitute of Medical Genetics, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UKSearch for more papers by this authorSong Han, Song Han Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorClaudia Consoli, Claudia Consoli Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorElisa Majounie, Elisa Majounie Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorMartin Horan, Martin Horan Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorNick S. Thomas, Nick S. Thomas Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorChristopher Potts, Christopher Potts Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorSian Griffiths, Sian Griffiths Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this authorMartino Ruggieri, Martino Ruggieri Institute of Bioimaging and Pathology of the Central Nervous System, National Research Council, Catania, ItalySearch for more papers by this authorAndreas von Deimling, Andreas von Deimling Institut für Neuropathologie, Charité, Humboldt-Universität, Berlin, GermanySearch for more papers by this authorDavid N. Cooper, David N. Cooper Institute of Medical Genetics, University of Wales College of Medicine, Cardiff, UKSearch for more papers by this author First published: 27 January 2004 https://doi.org/10.1002/humu.10305Citations: 80 † Communicated by Haig H. Kazazian AboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Abstract One of the main features of neurofibromatosis type 1 (NF1) is benign neurofibromas, 10–20% of which become transformed into malignant peripheral nerve sheath tumors (MPNSTs). The molecular basis of NF1 tumorigenesis is, however, still unclear. Ninety-one tumors from 31 NF1 patients were screened for gross changes in the NF1 gene using microsatellite/restriction fragment length polymorphism (RFLP) markers; loss of heterozygosity (LOH) was found in 17 out of 91 (19%) tumors (including two out of seven MPNSTs). Denaturing high performance liquid chromatography (DHPLC) was then used to screen 43 LOH-negative and 10 LOH-positive tumors for NF1 microlesions at both RNA and DNA levels. Thirteen germline and 12 somatic mutations were identified, of which three germline (IVS7–2A>G, 3731delT, 6117delG) and eight somatic (1888delG, 4374-4375delCC, R2129S, 2088delG, 2341del18, IVS27b–5C>T, 4083insT, Q519P) were novel. A mosaic mutation (R2429X) was also identified in a neurofibroma by DHPLC analysis and cloning/sequencing. The observed somatic and germline mutational spectra were similar in terms of mutation type, relative frequency of occurrence, and putative underlying mechanisms of mutagenesis. Tumors lacking mutations were screened for NF1 gene promoter hypermethylation but none were found. Microsatellite instability (MSI) analysis revealed MSI in five out of 11 MPNSTs as compared to none out of 70 neurofibromas (p=1.8 × 10−5). The screening of seven MPNSTs for subtle mutations in the CDKN2A and TP53 genes proved negative, although the screening of 11 MPNSTs detected LOH involving either the TP53 or the CDKN2A gene in a total of four tumors. These findings are consistent with the view that NF1 tumorigenesis is a complex multistep process involving a variety of different types of genetic defect at multiple loci. Hum Mutat 23:134–146, 2004. © 2003 Wiley-Liss, Inc. Citing Literature Supporting Information The Supplementary Material referred to in this article can be found at http://www.interscience.wiley.com/suppmat/1059-7794/suppmat/ Filename Description suppmat_134.pdf19 KB Supporting Information file suppmat_134.pdf Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article. Volume23, Issue2February 2004Pages 134-146 RelatedInformation