Genomes on the edge: how does genomic complexity drive cancer?

Although we are in the golden age of cancer genomics, with large volumes of sequencing data available, many fundamental aspects of tumour biology remain poorly understood. For example, over the past few years it has become clear that a variety of tumour types undergo catastrophic mutational events that generate complex rearrangements of the genome. These include chromothripsis, chromoplexy, breakage fusion bridges and ecDNAs (Hamdan and Ewing, 2022, J Pathol). We have shown these complex structural variants (CSVs) affect patient survival in high grade serous ovarian cancer (HGSOC), but the ways that genomic complexity affect disease progression are still poorly understood. We are now extending this large cohort to provide an unusual opportunity to study the functional impacts of CSVs and discover a new layer of therapeutic targets in the massively rearranged genomes of HGSOC tumours (Ewing et al, 2025, Nat Commun; see figure). In this project we will use bioinformatic approaches to discover the effects of CSVs on driver and ‘passenger’ gene expression in tumours, and understand how CSVs can modify tumour phenotypes as well as patient outcomes. The student undertaking this project will gain skills in bioinformatics and experience in cutting edge areas of cancer genomics.