title: Whole-genome characterization of chemoresistant 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.
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Ann-Marie
authors.initials: AM
authors.lastname: Patch
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Christie
authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Dariush
authors.initials: D
authors.lastname: Etemadmoghadam
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Dale W
authors.initials: DW
authors.lastname: Garsed
authors.affiliation: The Jackson Laboratory for Genomic Medicine, Farmington, Connecticut 06030, USA.
authors.forename: Joshy
authors.initials: J
authors.lastname: George
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Sian
authors.initials: S
authors.lastname: Fereday
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Katia
authors.initials: K
authors.lastname: Nones
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Prue
authors.initials: P
authors.lastname: Cowin
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Kathryn
authors.initials: K
authors.lastname: Alsop
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Bailey
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] Technology Advancement Unit, Genetics and Molecular Pathology, SA Pathology, Adelaide, South Australia 5000, Australia.
authors.forename: Karin S
authors.initials: KS
authors.lastname: Kassahn
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Felicity
authors.initials: F
authors.lastname: Newell
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Michael C J
authors.initials: MC
authors.lastname: Quinn
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Kazakoff
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Kelly
authors.initials: K
authors.lastname: Quek
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Wilhelm-Benartzi
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK.
authors.forename: Ed
authors.initials: E
authors.lastname: Curry
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Huei San
authors.initials: HS
authors.lastname: Leong
authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Medicine, University of Melbourne, Parkville, Victoria 3052, Australia [3] The Royal Women's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Anne
authors.initials: A
authors.lastname: Hamilton
authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Linda
authors.initials: L
authors.lastname: Mileshkin
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: George
authors.initials: G
authors.lastname: Au-Yeung
authors.affiliation: Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia.
authors.forename: Catherine
authors.initials: C
authors.lastname: Kennedy
authors.affiliation: Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia.
authors.forename: Jillian
authors.initials: J
authors.lastname: Hung
authors.affiliation: Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia.
authors.forename: Yoke-Eng
authors.initials: YE
authors.lastname: Chiew
authors.affiliation: Crown Princess Mary Cancer Centre and University of Sydney at Westmead Hospital, Westmead, Sydney, New South Wales 2145, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Harnett
authors.affiliation: Prince of Wales Clinical School, University of New South Wales, Sydney, New South Wales 2031, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Friedlander
authors.affiliation: The Royal Women's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Quinn
authors.affiliation: The Royal Women's Hospital, Parkville, Victoria 3052, Australia.
authors.forename: Jan
authors.initials: J
authors.lastname: Pyman
authors.affiliation: Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Cordner
authors.affiliation: Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia.
authors.forename: Patricia
authors.initials: P
authors.lastname: O'Brien
authors.affiliation: Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia.
authors.forename: Jodie
authors.initials: J
authors.lastname: Leditschke
authors.affiliation: Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia.
authors.forename: Greg
authors.initials: G
authors.lastname: Young
authors.affiliation: Victorian Institute of Forensic Medicine, Southbank, Victoria 3006, Australia.
authors.forename: Kate
authors.initials: K
authors.lastname: Strachan
authors.affiliation: Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Waring
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Walid
authors.initials: W
authors.lastname: Azar
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Chris
authors.initials: C
authors.lastname: Mitchell
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Nadia
authors.initials: N
authors.lastname: Traficante
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Joy
authors.initials: J
authors.lastname: Hendley
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Heather
authors.initials: H
authors.lastname: Thorne
authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Mark
authors.initials: M
authors.lastname: Shackleton
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Miller
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Gisela Mir
authors.initials: GM
authors.lastname: Arnau
authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: Richard W
authors.initials: RW
authors.lastname: Tothill
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Holloway
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Timothy
authors.initials: T
authors.lastname: Semple
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Ivon
authors.initials: I
authors.lastname: Harliwong
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Craig
authors.initials: C
authors.lastname: Nourse
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Ehsan
authors.initials: E
authors.lastname: Nourbakhsh
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Manning
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Senel
authors.initials: S
authors.lastname: Idrisoglu
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Timothy J C
authors.initials: TJ
authors.lastname: Bruxner
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Angelika N
authors.initials: AN
authors.lastname: Christ
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Barsha
authors.initials: B
authors.lastname: Poudel
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Oliver
authors.initials: O
authors.lastname: Holmes
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Matthew
authors.initials: M
authors.lastname: Anderson
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Conrad
authors.initials: C
authors.lastname: Leonard
authors.affiliation: Victorian Life Sciences Computation Initiative, Carlton, Victoria 3053, Australia.
authors.forename: Andrew
authors.initials: A
authors.lastname: Lonie
authors.affiliation: La Trobe Institute for Molecular Science, Bundoora, Victoria 3083, Australia.
authors.forename: Nathan
authors.initials: N
authors.lastname: Hall
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Scott
authors.initials: S
authors.lastname: Wood
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Darrin F
authors.initials: DF
authors.lastname: Taylor
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Qinying
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: J Lynn
authors.initials: JL
authors.lastname: Fink
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts 02115-5450, USA.
authors.forename: Ronny
authors.initials: R
authors.lastname: Drapkin
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK.
authors.forename: Euan
authors.initials: E
authors.lastname: Stronach
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK.
authors.forename: Hani
authors.initials: H
authors.lastname: Gabra
authors.affiliation: Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK.
authors.forename: Robert
authors.initials: R
authors.lastname: Brown
authors.affiliation: University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Andrea
authors.initials: A
authors.lastname: Jewell
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Shivashankar H
authors.initials: SH
authors.lastname: Nagaraj
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Emma
authors.initials: E
authors.lastname: Markham
authors.affiliation: Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Wilson
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Jason
authors.initials: J
authors.lastname: Ellul
authors.affiliation: Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia.
authors.forename: Orla
authors.initials: O
authors.lastname: McNally
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Maria A
authors.initials: MA
authors.lastname: Doyle
authors.affiliation: Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia.
authors.forename: Ravikiran
authors.initials: R
authors.lastname: Vedururu
authors.affiliation: The University of Western Australia, Crawley, Western Australia 6009, Australia.
authors.forename: Collin
authors.initials: C
authors.lastname: Stewart
authors.affiliation: University of Chicago, Chicago, Illinois 60637, USA.
authors.forename: Ernst
authors.initials: E
authors.lastname: Lengyel
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: John V
authors.initials: JV
authors.lastname: Pearson
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4006, Australia.
authors.forename: Nicola
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Centre for Cancer Research, University of Sydney at Westmead Millennium Institute, and Department of Gynaecological Oncology, Westmead Hospital, Sydney, New South Wales 2145, Australia.
authors.forename: Anna
authors.initials: A
authors.lastname: deFazio
authors.affiliation: 1] Queensland Centre for Medical Genomics, Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland 4067, Australia [2] WolfsonWohl Cancer Research Centre, Institute of Cancer Sciences, University of Glasgow, Glasgow G61 1QH, UK.
authors.forename: Sean M
authors.initials: SM
authors.lastname: Grimmond
authors.affiliation: 1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia [4] Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK [5] Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia.
authors.forename: David D L
authors.initials: DD
authors.lastname: Bowtell
mesh_terms: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000235:genetics; D015331:Cohort Studies; D019927:Cyclin E / Q000235:genetics; D018284:Cystadenocarcinoma, Serous / Q000188:drug therapy / Q000235:genetics; D019175:DNA Methylation; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins / Q000235:genetics; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics*; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D016514:Genes, Neurofibromatosis 1; D015894:Genome, Human / Q000235:genetics*; D018095:Germ-Line Mutation / Q000235:genetics; D006801:Humans; D016296:Mutagenesis / Q000235:genetics; D015513:Oncogene Proteins / Q000235:genetics; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics*; D051059:PTEN Phosphohydrolase / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics; D016160:Retinoblastoma Protein / Q000235:genetics
chemical_list: D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; C475820:CCNE1 protein, human; D019927:Cyclin E; D004268:DNA-Binding Proteins; D015513:Oncogene Proteins; C413002:RAD51B protein, human; D016160:Retinoblastoma Protein; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human