title: CASP9 germline mutation in a family with multiple brain tumors.
abstract: We report a novel CASP9 germline mutation that may increase susceptibility to the development of brain tumors. We identified this mutation in a family in which three brain tumors had developed within three generations, including two anaplastic astrocytomas occurring in cousins. The cousins were diagnosed at similar ages (29 and 31 years), and their tumors showed similar histological features. Genetic analysis revealed somatic IDH1 and TP53 mutations in both tumors. However, no germline TP53 mutations were detected, despite the fact that this family fulfills the criteria of Li-Fraumeni-like syndrome. Whole exome sequencing revealed a germline stop-gain mutation (R65X) in the CASP9 gene, which encodes caspase-9, a key molecule for the p53-dependent mitochondrial death pathway. This mutation was also detected in DNA extracted from blood samples from the two siblings who were each a parent of one of the affected cousins. Caspase-9 immunohistochemistry showed the absence of caspase-9 immunoreactivity in the anaplastic astrocytomas and normal brain tissues of the cousins. These observations suggest that CASP9 germline mutations may have played a role at least in part to the susceptibility of development of gliomas in this Li-Fraumeni-like family lacking a TP53 germline mutation.
authors.affiliation: Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Michael W
authors.identifier: http://orcid.org/0000-0002-1402-6290
authors.initials: MW
authors.lastname: Ronellenfitsch
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Oh
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Kaishi
authors.initials: K
authors.lastname: Satomi
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Koichiro
authors.initials: K
authors.lastname: Sumi
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Neurology (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Senckenberg Institute of Neurooncology, University Hospital Frankfurt, Frankfurt am Main, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
authors.affiliation: Department of Neuropathology, University of Düsseldorf, Düsseldorf, Germany.
authors.forename: Jörg
authors.initials: J
authors.lastname: Felsberg
authors.affiliation: Department of Neuropathology, University of Heidelberg, Heidelberg, Germany.|Clinical Cooperation Unit Neuropathology, German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: David
authors.initials: D
authors.lastname: Capper
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Catherine
authors.initials: C
authors.lastname: Voegele
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Durand
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: James
authors.initials: J
authors.lastname: McKay
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Florence
authors.initials: F
authors.lastname: Le Calvez-Kelm
authors.affiliation: Institute of Pathology and Neuropathology, Eberhard-Karls University of Tuebingen, Tuebingen, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Schittenhelm
authors.affiliation: German Cancer Research Center (DKFZ), Heidelberg, Germany.|Faculty of Medicine Carl Gustav Carus, TU Dresden, Institute for Clinical Genetics, Dresden, Germany.|German Cancer Consortium (DKTK), Dresden, Germany.|National Center for Tumor Diseases (NCT), Dresden, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klink
authors.affiliation: German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Institute of Neurology (Edinger Institute), Goethe University, Frankfurt am Main, Germany.
authors.forename: Michel
authors.initials: M
authors.lastname: Mittelbronn
authors.affiliation: International Agency for Research on Cancer (IARC), Lyon, France.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Ohgaki
mesh_terms: D000328:Adult; D001254:Astrocytoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D053453:Caspase 9 / Q000235:genetics*; D005190:Family; D005260:Female; D020022:Genetic Predisposition to Disease; D018095:Germ-Line Mutation; D006801:Humans
chemical_list: C506433:CASP9 protein, human; D053453:Caspase 9
keywords: CASP9; Li-Fraumeni-like syndrome; astrocytoma; exome sequencing