Whole-genome characterization of chemoresistant ovarian cancer

A.M. Patch, E.L. Christie, D. Etemadmoghadam, D.W. Garsed, J. George, S. Fereday, K. Nones, P. Cowin, K. Alsop, P.J. Bailey, K.S. Kassahn, F. Newell, M.C.J. Quinn, S. Kazakoff, K. Quek, C. Wilhelm-Benartzi, E. Curry, H.S. Leong, A. Hamilton, L. MileshkinG. Au-Yeung, C. Kennedy, J. Hung, Y.E. Chiew, P. Harnett, M. Friedlander, M. Quinn, J. Pyman, S. Cordner, P. O'Brien, J. Leditschke, G. Young, K. Strachan, P. Waring, W. Azar, C. Mitchell, N. Traficante, J. Hendley, H. Thorne, M. Shackleton, D.K. Miller, G.M. Arnau, R.W. Tothill, T.P. Holloway, T. Semple, I. Harliwong, C. Nourse, E. Nourbakhsh, S. Manning, S. Idrisoglu, T.J.C. Bruxner, A.N. Christ, B. Poudel, O. Holmes, M. Anderson, C. Leonard, A. Lonie, N. Hall, S. Wood, D.F. Taylor, Q. Xu, J. Lynn Fink, N. Waddell, R. Drapkin, E. Stronach, H. Gabra, R. Brown, A. Jewell, S.H. Nagaraj, E. Markham, P.J. Wilson, J. Ellul, O. Mcnally, M.A. Doyle, R. Vedururu, Colin Stewart, Yee Leung, E. Lengyel, A. Defazio, J.V. Pearson, S.M. Grimmond

    Research output: Contribution to journalArticle

    673 Citations (Scopus)

    Abstract

    © 2015 Macmillan Publishers Limited. All rights reserved. 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.
    Original languageEnglish
    Pages (from-to)489-494
    JournalNature
    Volume521
    Issue number7553
    DOIs
    Publication statusPublished - 2015

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