CHROMOTHRIPSIS

Dissecting the Molecular Mechanism of Catastrophic DNA Rearrangement in Cancer

Coordinatore	EUROPEAN MOLECULAR BIOLOGY LABORATORY    more Spiacenti, non ci sono informazioni su questo coordinatore. Contattare Fabio per maggiori infomrazioni, grazie.
Nazionalità Coordinatore	Germany [DE]
Totale costo	1˙496˙880 €
EC contributo	1˙496˙880 €
Programma	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)
Code Call	ERC-2013-StG
Funding Scheme	ERC-SG
Anno di inizio	2014
Periodo (anno-mese-giorno)	2014-04-01   -   2019-03-31

 Partecipanti

#	participant	country	role	EC contrib. [€]
1	EUROPEAN MOLECULAR BIOLOGY LABORATORY  Organization address address: Meyerhofstrasse 1 city: HEIDELBERG postcode: 69117 contact info Titolo: Dr. Nome: Jan Oliver Cognome: Korbel Email: send email Telefono: +49 6221 387 8822 Fax: +49 6221 387 8575	DE (HEIDELBERG)	hostInstitution	1˙496˙880.00
2	EUROPEAN MOLECULAR BIOLOGY LABORATORY  Organization address address: Meyerhofstrasse 1 city: HEIDELBERG postcode: 69117 contact info Titolo: Ms. Nome: Virginia Cognome: Otón García Email: send email Telefono: +49 6221 387 8535 Fax: +49 6221 387 8575	DE (HEIDELBERG)	hostInstitution	1˙496˙880.00

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 Obiettivo del progetto (Objective)

'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.'