"Cancer is commonly thought as a progressive process, requiring accumulation of many mutations over time. Recently, this conventional view of cancer progression has been challenged with the discovery of a phenomenon called chromothripsis, whereby tens to hundreds of chromosomal rearrangements occur in a single catastrophic event. Despite the growing amount of sequencing data that sheds some light on the nature of these structural variations, the molecular mechanisms behind these detrimental alterations are unclear. Here, I propose a research project aiming to decipher the mechanistic basis of chromothripsis. I will generate human cell lines with various genetic backgrounds that are prone to accumulate persistent DNA damage. With these cell lines in hand; I will systematically analyze the possible mechanisms leading to massive chromosome breakages. I will use laser microdissection to isolate the cells with potential chromosome breakages and further analyze them with flow karyotyping and deep sequencing. The experimental part of the proposed project will be complemented with detailed analyses of the existing genomic data in order to pinpoint mutations that could lead to chromothripsis. Together, this project will provide critical information on the molecular mechanisms behind this newly discovered catastrophic event and contribute to the understanding of cancer progression."