title: Braf Mutations Initiate the Development of Rat Gliomas Induced by Postnatal Exposure to N-Ethyl-N-Nitrosourea.
abstract: A single dose of N-ethyl-N-nitrosourea (ENU) during late prenatal or early postnatal development induces a high incidence of malignant schwannomas and gliomas in rats. Although T->A mutations in the transmembrane domain of the Neu (c-ErbB-2) gene are the driver mutations in ENU-induced malignant schwannomas, the molecular basis of ENU-induced gliomas remains enigmatic. We performed whole-genome sequencing of gliomas that developed in three BDIV and two BDIX rats exposed to a single dose of 80 mg ENU/kg body weight on postnatal day one. T:A->A:T and T:A->C:G mutations, which are typical for ENU-induced mutagenesis, were predominant (41% to 55% of all somatic single nucleotide mutations). T->A mutations were identified in all five rat gliomas at Braf codon 545 (V545E), which corresponds to the human BRAF V600E. Additional screening revealed that 33 gliomas in BDIV rats and 12 gliomas in BDIX rats all carried a Braf V545E mutation, whereas peritumoral brain tissue of either strain had the wild-type sequence. The gliomas were immunoreactive to BRAF V600E antibody. These results indicate that Braf mutation is a frequent early event in the development of rat gliomas caused by a single dose of ENU.
authors.affiliation: Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Qi
authors.initials: Q
authors.lastname: Wang
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Kaishi
authors.initials: K
authors.lastname: Satomi
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Ji Eun
authors.initials: JE
authors.lastname: Oh
authors.affiliation: Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Hutter
authors.affiliation: Division of Applied Bioinformatics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Brors
authors.affiliation: High Throughput Sequencing Unit, Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Nicolle
authors.initials: N
authors.lastname: Diessl
authors.affiliation: Division of Molecular Neurogenetics, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Hai-Kun
authors.initials: HK
authors.lastname: Liu
authors.affiliation: High Throughput Sequencing Unit, Genomics and Proteomics Core Facility, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Stephan
authors.initials: S
authors.lastname: Wolf
authors.affiliation: Helmholtz Association of German Research Centres, Berlin, Germany.
authors.forename: Otmar
authors.initials: O
authors.lastname: Wiestler
authors.affiliation: Faculty of Medicine, University of Zurich, Zurich, Switzerland.
authors.forename: Paul
authors.initials: P
authors.lastname: Kleihues
authors.affiliation: Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Koelsch
authors.affiliation: Institute of Pathology, University Hospital of Essen, University of Duisburg-Essen, Essen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Kindler-Röhrborn
authors.affiliation: International Agency for Research on Cancer, Lyon, France. Electronic address: ohgaki@iarc.fr.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohgaki
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D005038:Ethylnitrosourea / Q000009:adverse effects*; D005838:Genotype; D005910:Glioma / Q000139:chemically induced / Q000235:genetics*; D016296:Mutagenesis; D009442:Neurilemmoma / Q000139:chemically induced / Q000235:genetics*; D017354:Point Mutation; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D017422:Sequence Analysis, DNA
chemical_list: C482123:Braf protein, rat; D048493:Proto-Oncogene Proteins B-raf; D005038:Ethylnitrosourea