Repository logo
 

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

Accepted version
Peer-reviewed

Change log

Authors

Couturier, Dominique-Laurent  ORCID logo  https://orcid.org/0000-0001-5774-5036
Piskorz, Anna M 

Abstract

High-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, 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 tissues and 73 cell lines models, here we show that CA through centriole overduplication is a highly recurrent and heterogeneous feature of HGSOC and 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, the commonest 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.

Description

Keywords

Humans, Female, Ovarian Neoplasms, Paclitaxel, Centrosome, Cystadenocarcinoma, Serous

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

Publisher

Springer Science and Business Media LLC
Sponsorship
Cancer Research UK (A22905)
Cancer Research UK (C14303/A17197)
Cancer Research UK (24267)
Cancer Research UK (A25117)
National Institute for Health and Care Research (IS-BRC-1215-20014)
We acknowledge funding and support from Cancer Research UK, and the Cancer Research UK Cambridge Centre: A22905 (C.M.S., J.B.D.); A25177 (M.A.V.R), A25117 (K.H.). L.M.G. was supported by the Wellcome Trust PhD programme in Mathematical Genomics and Medicine (grant number RG92770). This research was also supported by the Ovarian Cancer Action (grant number 006; I.A.M.), and the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). Work in the Cancer Molecular Diagnostics Laboratory/Blood Processing Laboratory was supported by the NIHR Cambridge Biomedical Research Centre, Cancer Research UK Cambridge Centre and the Mark Foundation Institute for Integrated Cancer Medicine. The views expressed are those of the authors and not necessarily those of Cancer Research UK, the NIHR or the Department of Health and Social Care. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Relationships
Is supplemented by: