Molecular landscape and functional characterization of centrosome amplification in ovarian cancer

Abstract

AbstractHigh grade serous ovarian carcinoma (HGSOC) is characterised by poor outcome and extreme chromosome instability (CIN). Therapies targeting centrosome amplification (CA), a key mediator of chromosome missegregation and CIN, may have significant clinical utility in HGSOC. However, the prevalence of CA in HGSOC, its relationship to genomic biomarkers of CIN and its potential impact on therapeutic response have not been defined. Using high-throughput multi-regional microscopy on 287 clinical HGSOC tumour tissues and 73 ovarian cancer cell lines, we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and is strongly associated with CIN and genome subclonality. Cell-based studies showed that high prevalence CA is phenocopied in ovarian cancer cell lines, and that high CA is associated with increased multi-treatment resistance; most notably to paclitaxel which is the most common treatment used in HGSOC. CA in HGSOC may therefore present a potential driver of tumour evolution and a powerful biomarker for response to standard-of-care treatment.