Germline copy number variation of genes involved in chromatin remodelling in families suggestive of Li-Fraumeni syndrome with brain tumours
- 24 April 2013
- journal article
- research article
- Published by Springer Science and Business Media LLC in European Journal of Human Genetics
- Vol. 21 (12), 1369-1376
- https://doi.org/10.1038/ejhg.2013.68
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.This publication has 45 references indexed in Scilit:
- SIRT3 Functions in the Nucleus in the Control of Stress-Related Gene ExpressionMolecular and Cellular Biology, 2012
- MORC Family ATPases Required for Heterochromatin Condensation and Gene SilencingScience, 2012
- SIRT3 Is a Mitochondrial Tumor Suppressor: A Scientific Tale That Connects Aberrant Cellular ROS, the Warburg Effect, and CarcinogenesisCancer Research, 2012
- Germline copy number variations and cancer predispositionFuture Oncology, 2012
- Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastomaNature, 2012
- An RNAi Screen Identifies TRRAP as a Regulator of Brain Tumor-Initiating Cell DifferentiationCell Stem Cell, 2010
- MTA3, a Mi-2/NuRD Complex Subunit, Regulates an Invasive Growth Pathway in Breast CancerCell, 2003
- Transcriptional Regulation of the mdm2 Oncogene by p53 Requires TRRAP Acetyltransferase ComplexesMolecular and Cellular Biology, 2002
- Deacetylation of p53 modulates its effect on cell growth and apoptosisNature, 2000
- Induction of human cytotoxic T lymphocytes by artificial antigen-presenting cellsNature Biotechnology, 2000