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ERC

CHROMOTHRIPSIS Report Summary

Project ID: 336045
Funded under: FP7-IDEAS-ERC
Country: Germany

Mid-Term Report Summary - CHROMOTHRIPSIS (Dissecting the Molecular Mechanism of Catastrophic DNA Rearrangement in Cancer)

Recent cancer genome analyses have led to the discovery of a process involving massive genome structural rearrangement formation in a one-step, cataclysmic event, and coined chromothripsis. The term chromothripsis (chromo from chromosome; thripsis for shattering into pieces) stands for a proposed molecular process of as yet unknown mechanistic basis, in which individual chromosomes are thought to be pulverised resulting in a multitude of fragments, some of which are lost to the cell whereas others are erroneously rejoined. Aims of our ERC project are to dissect the mechanism behind chromothripsis using interdisciplinary approaches by (1) developing a computational approach to accurately detect chromothripsis, (2) using this approach to link chromothripsis with novel factors and contexts, (3) developing highly controllable cell line-based systems to test concrete mechanistic hypotheses, thereby taking into account our group’s data on linked factors and contexts, (4) generating transcriptome data to monitor pathways involved in inducing chromothripsis, and such involved in coping with the massive SRs occurring.

Initial work on defining criteria for uncovering chromothripsis in cancer genomes was published by us well after the submission of our ERC project application, but prior to the actual start of this ERC project on 01/04/2014 (Korbel & Campbell, Cell 2013, paper entitled “Criteria for inference of chromothripsis in cancer genomes.”). Based on these criteria, development of computational algorithms to automatize the analysis of chromothripsis in cancer genomes are currently well underway (WP1). In the context of WP2 we are presently in the process of pursuing cancer genome analyses at an unprecedented scale, with the aim to identify novel genetic factors and contexts (i.e. genomic context and tumor-subtype context) that are linked to chromothripsis. To facilitate fulfilling this aim, Jan Korbel has joined the steering committee of the Pan-Cancer Analysis of Whole Genomes (PCAWG) project (which we described in a recent perspective article published in Stein et al. Nature 2015), and is now co-leading this project, which will enable analysis of >2600 cancer genomes (sequenced by whole-genome sequencing) including numerous medulloblastoma and prostate cancer genomes to identify genetic factors and contexts linked with mutational processes including chromothripsis events. To efficiently detect and study the consequences of complex DNA rearrangements including chromothripsis events (WP3/WP4), we recently developed an integrative cell-based method termed Complex Alterations after Selection and Transformation (CAST), which uses cellular perturbations coupled with soft agar selection followed by massively-parallel sequencing, in the context of WP3. We employed this methodology to characterize catastrophic structural rearrangement formation processes including chromothripsis events, characterize their temporal sequence, as well as their impact on the transcriptome and on cell division. Additionally, given the availability of new efficient experimental protocols available to our laboratory, we also studied the influence of chromothripsis on the epigenome / structure of chromatin, in the context of WP3 and WP4. Using the CAST in vitro system, we identified a significantly increased rate of chromothripsis occuring in hyperploid cells. In addition, we also identified a link between telomere shortening and chromothripsis based on CAST (Mardin et al. Mol Sys Biol 2015), a very relevant finding that subsequently has been replicated elsewhere (Maciejowski et al. Cell 2015). Analysis of primary medulloblastoma cancer genomes (in the context of WP2), pursued by my group, have verified the link between hyperploidy and chromothripsis in vivo.

Reported by

EUROPEAN MOLECULAR BIOLOGY LABORATORY
Germany
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