Final Report Summary - BRM CHROMOTHRIPSIS (Dissecting Cancer Development by Chromothripsis Using Cell-Based Models)
Overall aim of this research project was to investigate the molecular mechanisms of chromothripsis by generation, screening and evaluation of somatic structural variants in vitro. For this reason, we generated human cell lines with various genetic backgrounds that were prone to accumulate persistent DNA damage and were therefore used for a systematic analysis on potential mechanisms leading to massive chromosome breakages. We applied an integrative approach enabling efficient generation of complex structural DNA rearrangements in vitro by perturbing karyotypically normal cells and subsequent analysis by massively-parallel sequencing. Following this approach, we reproducibly produced cell lines exhibiting this catastrophical phenomenon, i.e. chromothripsis, and analyzed them in detail.
The occurrence of chromothripsis was apparent at a significant propensity in cells with specific genetic backgrounds. Our findings in vitro were confirmed in vivo analyzing primary human cancer genomes. Taken together, the results of this project provide critical information on the molecular mechanisms behind chromothripsis and set a foundation for future mechanistic studies, which might contribute to the understanding of cancer progression.