title: Somatic neurofibromatosis type 1 (NF1) inactivation events in cutaneous neurofibromas of a single NF1 patient.
abstract: Neurofibromatosis type 1 (NF1) (MIM#162200) is a relatively frequent genetic condition that predisposes to tumor formation. The main types of tumors occurring in NF1 patients are cutaneous and subcutaneous neurofibromas, plexiform neurofibromas, optic pathway gliomas, and malignant peripheral nerve sheath tumors. To search for somatic mutations in cutaneous (dermal) neurofibromas, whole-exome sequencing (WES) was performed on seven spatially separated tumors and two reference tissues (blood and unaffected skin) from a single NF1 patient. Validation of WES findings was done using routine Sanger sequencing or Sequenom IPlex SNP genotyping. Exome sequencing confirmed the existence of a known familial splice-site mutation NM_000267.3:c.3113+1G>A in exon 23 of NF1 gene (HGMD ID CS951480) in blood, unaffected skin, and all tumor samples. In five out of seven analyzed tumors, we additionally detected second-hit mutations in the NF1 gene. Four of them were novel and one was previously observed. Each mutation was distinct, demonstrating the independent origin of each tumor. Only in two of seven tumors we detected an additional somatic mutation that was not associated with NF1. Our study demonstrated that somatic mutations of NF1 are likely the main drivers of cutaneous tumor formation. The study provides evidence for the rareness of single base pair level alterations in the exomes of benign NF1 cutaneous tumors.
authors.affiliation: 1] FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Institute for Medical Genetics and Human Genetics, Universitätsmedizin Berlin, Charité Berlin - Campus Virchow, Berlin, Germany.
authors.forename: Denise
authors.initials: D
authors.lastname: Emmerich
authors.affiliation: 1] Institute for Medical Genetics and Human Genetics, Universitätsmedizin Berlin, Charité Berlin - Campus Virchow, Berlin, Germany [2] Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany [3] Institute of Bioorganic Chemistry, Polish Academy of Sciences, Poznan, Poland.
authors.forename: Tomasz
authors.initials: T
authors.lastname: Zemojtel
authors.affiliation: 1] FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Krawitz
authors.affiliation: FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Malte
authors.initials: M
authors.lastname: Spielmann
authors.affiliation: 1] FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Institute for Medical Genetics and Human Genetics, Universitätsmedizin Berlin, Charité Berlin - Campus Virchow, Berlin, Germany.
authors.forename: Jirko
authors.initials: J
authors.lastname: Kühnisch
authors.affiliation: FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Karolina
authors.initials: K
authors.lastname: Kobus
authors.affiliation: FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Osswald
authors.affiliation: Institute for Medical Genetics and Human Genetics, Universitätsmedizin Berlin, Charité Berlin - Campus Virchow, Berlin, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Heinrich
authors.affiliation: Center for Laser Medicine, Evangelic Elisabeth Clinic, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Berlien
authors.affiliation: Center for Laser Medicine, Evangelic Elisabeth Clinic, Berlin, Germany.
authors.forename: Ute
authors.initials: U
authors.lastname: Müller
authors.affiliation: Department of Maxillofacial Surgery, University Hospital Eppendorf, Hamburg, Germany.
authors.forename: Victor-F
authors.initials: VF
authors.lastname: Mautner
authors.affiliation: Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria.
authors.forename: Katharina
authors.initials: K
authors.lastname: Wimmer
authors.affiliation: Institute for Medical Genetics and Human Genetics, Universitätsmedizin Berlin, Charité Berlin - Campus Virchow, Berlin, Germany.
authors.forename: Peter N
authors.initials: PN
authors.lastname: Robinson
authors.affiliation: Computational Molecular Biology, Max Planck Institute for Molecular Genetics, Berlin, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Vingron
authors.affiliation: 1] Division of Human Genetics, Medical University Innsbruck, Innsbruck, Austria [2] Institute of Clinical Genetics, Carl Gustav Carus Medical Academy, Technical University, Dresden, Germany.
authors.forename: Sigrid
authors.initials: S
authors.lastname: Tinschert
authors.affiliation: 1] FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Institute for Medical Genetics and Human Genetics, Universitätsmedizin Berlin, Charité Berlin - Campus Virchow, Berlin, Germany [3] Berlin-Brandenburg Center for Regenerative Therapies (BCRT), Berlin, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mundlos
authors.affiliation: 1] FG Development & Disease, Max Planck Institute for Molecular Genetics, Berlin, Germany [2] Institute for Medical Genetics and Human Genetics, Universitätsmedizin Berlin, Charité Berlin - Campus Virchow, Berlin, Germany.
authors.forename: Mateusz
authors.initials: M
authors.lastname: Kolanczyk
mesh_terms: D060965:Clonal Evolution; D059472:Exome; D005260:Female; D006801:Humans; D008875:Middle Aged; D009154:Mutation; D009456:Neurofibromatosis 1 / Q000235:genetics*; D025542:Neurofibromin 1 / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D012878:Skin Neoplasms / Q000235:genetics*
chemical_list: D025542:Neurofibromin 1