1. Whole-genome characterization of chemoresistant ovarian cancer
- Author
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Catherine Kennedy, Peter Bailey, Michael Friedlander, Conrad Leonard, Euan A. Stronach, Jodie Leditschke, Prue A. Cowin, Darrin Taylor, David D.L. Bowtell, Chris Mitchell, Felicity Newell, Senel Idrisoglu, Ravikiran Vedururu, Kathryn Alsop, Ehsan Nourbakhsh, Patricia C. M. O’Brien, Nathan E. Hall, Collin Stewart, Ann-Marie Patch, Linda Mileshkin, Gisela Mir Arnau, Charlotte Wilhelm-Benartzi, Shivashankar H. Nagaraj, Nadia Traficante, Angelika N. Christ, Edward Curry, Qinying Xu, Stephen H. Kazakoff, Emma Markham, Kate Strachan, Timothy J. C. Bruxner, David Miller, Nick Waddell, Yoke Eng Chiew, Karin S. Kassahn, A. Jewell, Barsha Poudel, Ronny Drapkin, Ernst Lengyel, Oliver Holmes, George Au-Yeung, Joshy George, Kelly Quek, Richard W. Tothill, Orla McNally, John V. Pearson, J. Lynn Fink, Greg Young, Nicola Waddell, Elizabeth L. Christie, Jillian Hung, Michael C. J. Quinn, Ivon Harliwong, Jan Pyman, Jason Ellul, Walid J Azar, Katia Nones, Andrew Lonie, Sian Fereday, Craig Nourse, Stephen Cordner, Dariush Etemadmoghadam, Anna deFazio, Paul R. Harnett, Scott Wood, Maria A. Doyle, Michael C.J. Quinn, Robert S. Brown, Hani Gabra, Peter Wilson, Joy Hendley, Timothy P. Holloway, Sean M. Grimmond, Heather Thorne, Matthew J. Anderson, Mark Shackleton, Suzanne Manning, Anne Hamilton, Dale W. Garsed, Huei San Leong, Timothy Semple, and Paul Waring
- Subjects
DNA Mutational Analysis ,Genes, BRCA2 ,Genes, BRCA1 ,Drug resistance ,Biology ,Retinoblastoma Protein ,Germline ,Cohort Studies ,Germline mutation ,Cyclin E ,Genes, Neurofibromatosis 1 ,medicine ,PTEN ,Humans ,ATP Binding Cassette Transporter, Subfamily B, Member 1 ,Promoter Regions, Genetic ,Germ-Line Mutation ,Genetics ,Oncogene Proteins ,Ovarian Neoplasms ,Multidisciplinary ,Genome, Human ,PTEN Phosphohydrolase ,Combination chemotherapy ,DNA Methylation ,medicine.disease ,Cystadenocarcinoma, Serous ,DNA-Binding Proteins ,Serous fluid ,Drug Resistance, Neoplasm ,Mutagenesis ,DNA methylation ,Cancer research ,biology.protein ,Female ,Ovarian cancer - 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.
- Published
- 2014