title: Germline copy number variation of genes involved in chromatin remodelling in families suggestive of Li-Fraumeni syndrome with brain tumours.
abstract: Germline alterations of the tumour suppressor TP53 gene are detected approximately in 25% of the families suggestive of Li-Fraumeni syndrome (LFS), characterised by a genetic predisposition to a wide tumour spectrum, including soft-tissue sarcomas, osteosarcomas, premenopausal breast cancers, brain tumours, adrenocortical tumours, plexus choroid tumours, leukaemia and lung cancer. The aim of this study was to determine the contribution of germline copy number variations (CNVs) to LFS in families without detectable TP53 mutation. Using a custom-designed high-resolution array CGH, we evaluated the presence of rare germline CNVs in 64 patients fulfilling the Chompret criteria for LFS, but without any detectable TP53 alteration. In 15 unrelated patients, we detected 20 new CNVs absent in 600 controls. Remarkably, in four patients who had developed each brain tumour, the detected CNV overlap the KDM1A, MTA3, TRRAP or SIRT3 genes encoding p53 partners involved in histone methylation or acetylation. Focused analysis of SIRT3 showed that the CNV encompassing SIRT3 leads to SIRT3 overexpression, and that in vitro SIRT3 overexpression prevents apoptosis, increases G2/M and results in a hypermethylation of numerous genes. This study supports the causal role of germline alterations of genes involved in chromatin remodelling in genetic predisposition to cancer and, in particular, to brain tumours.
authors.affiliation: 1] Inserm, U1079, Faculty of Medicine, University of Rouen, Rouen, France [2] Institute for Research and Innovation in Biomedicine, University of Rouen, Rouen, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Aury-Landas
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Bougeard
authors.forename: Hélène
authors.initials: H
authors.lastname: Castel
authors.forename: Hector
authors.initials: H
authors.lastname: Hernandez-Vargas
authors.forename: Aurélie
authors.initials: A
authors.lastname: Drouet
authors.forename: Jean-Baptiste
authors.initials: JB
authors.lastname: Latouche
authors.forename: Marie-Thérèse
authors.initials: MT
authors.lastname: Schouft
authors.forename: Claude
authors.initials: C
authors.lastname: Férec
authors.forename: Dominique
authors.initials: D
authors.lastname: Leroux
authors.forename: Christine
authors.initials: C
authors.lastname: Lasset
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coupier
authors.forename: Olivier
authors.initials: O
authors.lastname: Caron
authors.forename: Zdenko
authors.initials: Z
authors.lastname: Herceg
authors.forename: Thierry
authors.initials: T
authors.lastname: Frebourg
authors.forename: Jean-Michel
authors.initials: JM
authors.lastname: Flaman
mesh_terms: D000107:Acetylation; D000293:Adolescent; D017209:Apoptosis / Q000235:genetics; D001932:Brain Neoplasms / Q000235:genetics*; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics*; D056915:DNA Copy Number Variations / Q000235:genetics*; D019175:DNA Methylation / Q000235:genetics; D005260:Female; D018095:Germ-Line Mutation / Q000235:genetics*; D006801:Humans; D016864:Li-Fraumeni Syndrome / Q000235:genetics*; D008297:Male; D056566:Sirtuin 3 / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
chemical_list: D002843:Chromatin; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C466093:SIRT3 protein, human; D056566:Sirtuin 3