| Literature DB >> 26017449 |
Ann-Marie Patch1, Elizabeth L Christie2, Dariush Etemadmoghadam3, Dale W Garsed2, Joshy George4, Sian Fereday2, Katia Nones1, Prue Cowin2, Kathryn Alsop2, Peter J Bailey5, Karin S Kassahn6, Felicity Newell7, Michael C J Quinn1, Stephen Kazakoff1, Kelly Quek7, Charlotte Wilhelm-Benartzi8, Ed Curry8, Huei San Leong2, Anne Hamilton9, Linda Mileshkin10, George Au-Yeung2, Catherine Kennedy11, Jillian Hung11, Yoke-Eng Chiew11, Paul Harnett12, Michael Friedlander13, Michael Quinn14, Jan Pyman14, Stephen Cordner15, Patricia O'Brien15, Jodie Leditschke15, Greg Young15, Kate Strachan15, Paul Waring16, Walid Azar2, Chris Mitchell2, Nadia Traficante2, Joy Hendley2, Heather Thorne2, Mark Shackleton10, David K Miller7, Gisela Mir Arnau2, Richard W Tothill10, Timothy P Holloway2, Timothy Semple2, Ivon Harliwong7, Craig Nourse7, Ehsan Nourbakhsh7, Suzanne Manning7, Senel Idrisoglu7, Timothy J C Bruxner7, Angelika N Christ7, Barsha Poudel7, Oliver Holmes1, Matthew Anderson7, Conrad Leonard1, Andrew Lonie17, Nathan Hall18, Scott Wood1, Darrin F Taylor7, Qinying Xu1, J Lynn Fink7, Nick Waddell7, Ronny Drapkin19, Euan Stronach8, Hani Gabra8, Robert Brown8, Andrea Jewell20, Shivashankar H Nagaraj7, Emma Markham7, Peter J Wilson7, Jason Ellul2, Orla McNally11, Maria A Doyle2, Ravikiran Vedururu2, Collin Stewart21, Ernst Lengyel20, John V Pearson1, Nicola Waddell1, Anna deFazio11, Sean M Grimmond5, David D L Bowtell22.
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.Entities:
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Year: 2015 PMID： 26017449 DOI： 10.1038/nature14410
Source DB: PubMed Journal: Nature ISSN： 0028-0836 Impact factor: 49.962