Objetivo Recent cancer genome analyses have led to the discovery of a process involving massive genome structural rearrangement (SR) formation in a one-step, cataclysmic event, coined chromothripsis. The term chromothripsis (chromo from chromosome; thripsis for shattering into pieces) stands for a hypothetical process in which individual chromosomes are pulverised, resulting in a multitude of fragments, some of which are lost to the cell whereas others are erroneously rejoined. Compelling evidence was presented that chromothripsis plays a crucial role in the development, or progression of a notable subset of human cancers – thus, tumorigensis models involving gradual acquisitions of alterations may need to be revised in these cancers.Presently, chromothripsis lacks a mechanistic basis. We recently showed that in childhood medulloblastoma brain tumours driven by Sonic Hedgehog (Shh) signalling, chromothripsis is linked with predisposing TP53 mutations. Thus, rather than occurring in isolation, chromothripsis appears to be prone to happen in conjunction with (or instigated by) gradually acquired alterations, or in the context of active signalling pathways, the inference of which may lead to further mechanistic insights. Using such rationale, I propose to dissect the mechanism behind chromothripsis using interdisciplinary approaches. First, we will develop a computational approach to accurately detect chromothripsis. Second, we will use this approach to link chromothripsis with novel factors and contexts. Third, we will develop highly controllable cell line-based systems to test concrete mechanistic hypotheses, thereby taking into account our data on linked factors and contexts. Fourth, we will generate transcriptome data to monitor pathways involved in inducing chromothripsis, and such involved in coping with the massive SRs occurring. We will also combine findings from all these approaches to build a comprehensive model of chromothripsis and its associated pathways. Ámbito científico natural sciencesbiological sciencesgeneticsDNAnatural sciencesbiological sciencesgeneticsmutationmedical and health sciencesclinical medicineoncologynatural sciencesbiological sciencesgeneticschromosomesnatural sciencesbiological sciencesgeneticsgenomes Programa(s) FP7-IDEAS-ERC - Specific programme: "Ideas" implementing the Seventh Framework Programme of the European Community for research, technological development and demonstration activities (2007 to 2013) Tema(s) ERC-SG-LS2 - ERC Starting Grant - Genetics,Genomics,Bioinformatics and Systems Biology Convocatoria de propuestas ERC-2013-StG Consulte otros proyectos de esta convocatoria Régimen de financiación ERC-SG - ERC Starting Grant Institución de acogida EUROPEAN MOLECULAR BIOLOGY LABORATORY Aportación de la UE € 1 471 964,05 Dirección Meyerhofstrasse 1 69117 Heidelberg Alemania Ver en el mapa Región Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Tipo de actividad Research Organisations Contacto administrativo Virginia Otón García (Ms.) Investigador principal Jan Oliver Korbel (Dr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos Beneficiarios (1) Ordenar alfabéticamente Ordenar por aportación de la UE Ampliar todo Contraer todo EUROPEAN MOLECULAR BIOLOGY LABORATORY Alemania Aportación de la UE € 1 471 964,05 Dirección Meyerhofstrasse 1 69117 Heidelberg Ver en el mapa Región Baden-Württemberg Karlsruhe Heidelberg, Stadtkreis Tipo de actividad Research Organisations Contacto administrativo Virginia Otón García (Ms.) Investigador principal Jan Oliver Korbel (Dr.) Enlaces Contactar con la organización Opens in new window Sitio web Opens in new window Coste total Sin datos