학술논문
Molecular landscape and functional characterization of centrosome amplification in ovarian cancer
Document Type
article
Author
Carolin M. Sauer; James A. Hall; Dominique-Laurent Couturier; Thomas Bradley; Anna M. Piskorz; Jacob Griffiths; Ashley Sawle; Matthew D. Eldridge; Philip Smith; Karen Hosking; Marika A. V. Reinius; Lena Morrill Gavarró; Anne-Marie Mes-Masson; Darren Ennis; David Millan; Aoisha Hoyle; Iain A. McNeish; Mercedes Jimenez-Linan; Filipe Correia Martins; Julia Tischer; Maria Vias; James D. Brenton
Source
Nature Communications, Vol 14, Iss 1, Pp 1-20 (2023)
Subject
Language
English
ISSN
2041-1723
Abstract
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.