title: Mutational inactivation of the nijmegen breakage syndrome gene (NBS1) in glioblastomas is associated with multiple TP53 mutations.
abstract: Nijmegen breakage syndrome caused by NBS1 germline mutations is a rare autosomal recessive disease with clinical features that include microcephaly, increased radiosensitivity, and predisposition to cancer. NBS1 plays a key role in DNA double-strand break repair and the maintenance of genomic stability. We screened 87 glioblastomas for NBS1 mutations (all 16 exons). Single-strand conformation polymorphism followed by direct DNA sequencing revealed 12 NBS1 mutations (8 missense and 4 intronic mutations) in 9 (32%) of 28 primary (de novo) glioblastomas carrying 2 or more TP53 mutations. None of the NBS1 mutations has been previously reported as a germline mutation in Nijmegen breakage syndrome patients. NBS1 mutations were not detected in 19 primary glioblastomas with 1 TP53 mutation or in 21 primary glioblastomas without TP53 mutations. Secondary glioblastomas that developed through progression from low-grade or anaplastic astrocytoma had TP53 mutations in 16 (84%) of 19 cases, but none contained mutations of the NBS1 gene. These results suggest that multiple TP53 mutations in glioblastomas are due to deficient repair of DNA double-strand breaks caused by mutational inactivation of the NBS1 gene.
authors.affiliation: International Agency for Research on Cancer, Lyon, France.
authors.forename: Takuya
authors.initials: T
authors.lastname: Watanabe
authors.forename: Sumihito
authors.initials: S
authors.lastname: Nobusawa
authors.forename: Shengqing
authors.initials: S
authors.lastname: Lu
authors.forename: Jian
authors.initials: J
authors.lastname: Huang
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohgaki
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D004260:DNA Repair / Q000235:genetics; D018450:Disease Progression; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D020868:Gene Silencing / Q000502:physiology*; D016158:Genes, p53 / Q000235:genetics*; D020022:Genetic Predisposition to Disease / Q000235:genetics; D005820:Genetic Testing; D005838:Genotype; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism / Q000503:physiopathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics
chemical_list: D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins