作者
Ann‐Marie Patch,Elizabeth L. Christie,Dariush Etemadmoghadam,Dale W. Garsed,Joshy George,Sián Fereday,Kátia Nones,Prue A. Cowin,Kathryn Alsop,Peter J. Bailey,Karin S. Kassahn,Felicity Newell,Michael C. Quinn,Stephen H. Kazakoff,Kelly Quek,Charlotte Wilhelm-Benartzi,Ed Curry,Huei San Leong,Anne Hamilton,Linda Mileshkin,George Au-Yeung,Catherine J. Kennedy,Jillian Hung,Yoke Eng Chiew,Paul Harnett,Michael Friedlander,Jan Pyman,Stephen Cordner,Patricia J. O′Brien,Jodie Leditschke,Greg Young,Kate Strachan,Paul Waring,Walid J. Azar,Chris Mitchell,Nadia Traficante,Joy Hendley,Heather Thorne,Mark Shackleton,David 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 E. Hall,Scott Wood,Darrin Taylor,Qinying Xu,J. Lynn Fink,Nick M. Waddell,Ronny Drapkin,Euan A. Stronach,Hani Gabra,Robert E. Brown,Andrea Jewell,Shivashankar H. Nagaraj,Emma Markham,Peter J. Wilson,Jason Ellul,Orla McNally,Maria Doyle,Ravikiran Vedururu,Collin Stewart,Ernst Lengyel,John V. Pearson,Nicola Waddell,Anna deFazio,Sean M. Grimmond,David D.L. Bowtell
摘要
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.