title: TP53, MSH4, and LATS1 germline mutations in a family with clustering of nervous system tumors.
abstract: Exome DNA sequencing of blood samples from a Li-Fraumeni family with a TP53 germline mutation (codon 236 deletion) and multiple nervous system tumors revealed additional germline mutations. Missense mutations in the MSH4 DNA repair gene (c.2480T>A; p.I827N) were detected in three patients with gliomas (two anaplastic astrocytomas, two glioblastomas). Two family members without a TP53 germline mutation who developed peripheral schwannomas also carried the MSH4 germline mutation, and in addition, a germline mutation of the LATS1 gene (c.286C>T; p.R96W). LATS1 is a downstream mediator of the NF2, but has not previously been found to be related to schwannomas. We therefore screened the entire coding sequence of the LATS1 gene in 65 sporadic schwannomas, 12 neurofibroma/schwannoma hybrid tumors, and 4 cases of schwannomatosis. We only found a single base deletion at codon 827 (exon 5) in a spinal schwannoma, leading to a stop at codon 835 (c.2480delG; p.*R827Kfs*8). Mutational loss of LATS1 function may thus play a role in some inherited schwannomas, but only exceptionally in sporadic schwannomas. This is the first study reporting a germline MSH4 mutation. Since it was present in all patients, it may have contributed to the subsequent acquisition of TP53 and LATS1 germline mutations.
authors.affiliation: Section of Molecular Pathology, International Agency for Research on Cancer, Lyon, France; Translational Epidemiology Research Branch, National Cancer Center, Goyang, Republic of Korea.
authors.forename: Young-Ho
authors.initials: YH
authors.lastname: Kim
authors.affiliation: Section of Molecular Pathology, International Agency for Research on Cancer, Lyon, France.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ohta
authors.affiliation: Section of Molecular Pathology, International Agency for Research on Cancer, Lyon, France.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Oh
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: James
authors.initials: J
authors.lastname: McKay
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Voegele
authors.affiliation: Group of Genetic Cancer Susceptibility, International Agency for Research on Cancer, Lyon, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Durand
authors.affiliation: Institute of Neurology (Edinger Institute), Johann Wolfgang Goethe University Frankfurt, Frankfurt/Main, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: Medical Faculty, University of Zürich, Zürich, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Kleihues
authors.affiliation: Institute of Neuropathology, University Hospital Münster, Münster, Germany.
authors.forename: Werner
authors.initials: W
authors.lastname: Paulus
authors.affiliation: Section of Molecular Pathology, International Agency for Research on Cancer, Lyon, France. Electronic address: ohgaki@iarc.fr.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohgaki
mesh_terms: D000328:Adult; D001483:Base Sequence; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics; D008297:Male; D053842:Microsatellite Instability; D008969:Molecular Sequence Data; D009423:Nervous System Neoplasms / Q000235:genetics*; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; C409221:MSH4 protein, human; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C092745:LATS1 protein, human; D017346:Protein Serine-Threonine Kinases