Molecular landscape and functional characterization of centrosome amplification in 1 ovarian cancer

High grade serous ovarian carcinoma (HGSOC) is the major cause of gynaecological cancer-related deaths in the Western world, and is characterised by extreme chromosomal instability (CIN). CIN is a key mediator of clonal diversity and treatment resistance and is associated with poor disease outcome. An increased understanding of underlying mechanisms driving CIN in HGSOC is therefore critical to predict outcomes and identify novel therapeutic approaches. The centrosome is the main microtubule organising centre of a cell and plays a crucial role during cell division and chromosome segregation. Missegregation of chromosomes at high rates results in CIN; and supernumerary centrosomes have previously been associated with aneuploidy and poor disease outcome in several cancers. However, relatively little is currently known about centrosome abnormalities and associated molecular features in HGSOC. Here, we developed high-throughput microscopy approaches to provide the first large-scale characterisation of centrosome amplification (CA) in >300 clinical tissue samples and >70 ovarian cancer cell lines. We report that HGSOC frequently shows supernumerary centrosomes with marked intra-tissue heterogeneity. Imaging and shallow whole genome sequencing experiments further revealed that CA in HGSOC is associated with the presence of micronuclei, increased genomic abnormality and, interestingly, genomic subclonality, highlighting CA as a potential driver of tumour evolution. Further, using RNA sequencing, and drug assays on selected cell lines we found that cells with high CA show upregulated NFκB signalling and increased resistance to standard-of-care paclitaxel as well as other therapeutic agents. In addition, our detailed phenotypic, genomic, and transcriptomic characterisation of >70 ovarian cancer cell lines will provide an important platform for future studies on CIN and CA in ovarian cancer.