Whole–genome characterization of chemoresistant ovarian cancer View Full Text


Ontology type: schema:ScholarlyArticle     


Article Info

DATE

2015-05

AUTHORS

Ann-Marie Patch, Elizabeth L. Christie, Dariush Etemadmoghadam, Dale W. Garsed, Joshy George, Sian Fereday, Katia Nones, Prue Cowin, Kathryn Alsop, Peter J. Bailey, Karin S. Kassahn, Felicity Newell, Michael C. J. Quinn, Stephen Kazakoff, Kelly Quek, Charlotte Wilhelm-Benartzi, Ed Curry, Huei San Leong, The Australian Ovarian Cancer Study Group, Anne Hamilton, Linda Mileshkin, George Au-Yeung, Catherine Kennedy, Jillian Hung, Yoke-Eng Chiew, Paul Harnett, Michael Friedlander, Michael Quinn, Jan Pyman, Stephen Cordner, Patricia O’Brien, Jodie Leditschke, Greg Young, Kate Strachan, Paul Waring, Walid Azar, Chris Mitchell, Nadia Traficante, Joy Hendley, Heather Thorne, Mark Shackleton, David K. Miller, Gisela Mir Arnau, Richard W. Tothill, Timothy P. Holloway, Timothy Semple, Ivon Harliwong, Craig Nourse, Ehsan Nourbakhsh, Suzanne Manning, Senel Idrisoglu, Timothy J. C. Bruxner, Angelika N. Christ, Barsha Poudel, Oliver Holmes, Matthew Anderson, Conrad Leonard, Andrew Lonie, Nathan Hall, Scott Wood, Darrin F. Taylor, Qinying Xu, J. Lynn Fink, Nick Waddell, Ronny Drapkin, Euan Stronach, Hani Gabra, Robert Brown, Andrea Jewell, Shivashankar H. Nagaraj, Emma Markham, Peter J. Wilson, Jason Ellul, Orla McNally, Maria A. Doyle, Ravikiran Vedururu, Collin Stewart, Ernst Lengyel, John V. Pearson, Nicola Waddell, Anna deFazio, Sean M. Grimmond, David D. L. Bowtell

ABSTRACT

Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA samples from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 amplification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in individual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1. More... »

PAGES

489

References to SciGraph publications

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/nature14410

    DOI

    http://dx.doi.org/10.1038/nature14410

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1051129444

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26017449


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