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. Mileshkin & 61 others G. 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

    479 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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    Chemotherapy
    Refractory materials
    Tumors
    Genes
    Methylation
    Amplification
    Platinum
    DNA
    Fusion reactions
    Pumps

    Cite this

    Patch, A. M., Christie, E. L., Etemadmoghadam, D., Garsed, D. W., George, J., Fereday, S., ... Grimmond, S. M. (2015). Whole-genome characterization of chemoresistant ovarian cancer. Nature, 521(7553), 489-494. https://doi.org/10.1038/nature14410
    Patch, A.M. ; Christie, E.L. ; Etemadmoghadam, D. ; Garsed, D.W. ; George, J. ; Fereday, S. ; Nones, K. ; Cowin, P. ; Alsop, K. ; Bailey, P.J. ; Kassahn, K.S. ; Newell, F. ; Quinn, M.C.J. ; Kazakoff, S. ; Quek, K. ; Wilhelm-Benartzi, C. ; Curry, E. ; Leong, H.S. ; Hamilton, A. ; Mileshkin, L. ; Au-Yeung, G. ; Kennedy, C. ; Hung, J. ; Chiew, Y.E. ; Harnett, P. ; Friedlander, M. ; Quinn, M. ; Pyman, J. ; Cordner, S. ; O'Brien, P. ; Leditschke, J. ; Young, G. ; Strachan, K. ; Waring, P. ; Azar, W. ; Mitchell, C. ; Traficante, N. ; Hendley, J. ; Thorne, H. ; Shackleton, M. ; Miller, D.K. ; Arnau, G.M. ; Tothill, R.W. ; Holloway, T.P. ; Semple, T. ; Harliwong, I. ; Nourse, C. ; Nourbakhsh, E. ; Manning, S. ; Idrisoglu, S. ; Bruxner, T.J.C. ; Christ, A.N. ; Poudel, B. ; Holmes, O. ; Anderson, M. ; Leonard, C. ; Lonie, A. ; Hall, N. ; Wood, S. ; Taylor, D.F. ; Xu, Q. ; Lynn Fink, J. ; Waddell, N. ; Drapkin, R. ; Stronach, E. ; Gabra, H. ; Brown, R. ; Jewell, A. ; Nagaraj, S.H. ; Markham, E. ; Wilson, P.J. ; Ellul, J. ; Mcnally, O. ; Doyle, M.A. ; Vedururu, R. ; Stewart, Colin ; Leung, Yee ; Lengyel, E. ; Defazio, A. ; Pearson, J.V. ; Grimmond, S.M. / Whole-genome characterization of chemoresistant ovarian cancer. In: Nature. 2015 ; Vol. 521, No. 7553. pp. 489-494.
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    title = "Whole-genome characterization of chemoresistant ovarian cancer",
    abstract = "{\circledC} 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.",
    author = "A.M. Patch and E.L. Christie and D. Etemadmoghadam and D.W. Garsed and J. George and S. Fereday and K. Nones and P. Cowin and K. Alsop and P.J. Bailey and K.S. Kassahn and F. Newell and M.C.J. Quinn and S. Kazakoff and K. Quek and C. Wilhelm-Benartzi and E. Curry and H.S. Leong and A. Hamilton and L. Mileshkin and G. Au-Yeung and C. Kennedy and J. Hung and Y.E. Chiew and P. Harnett and M. Friedlander and M. Quinn and J. Pyman and S. Cordner and P. O'Brien and J. Leditschke and G. Young and K. Strachan and P. Waring and W. Azar and C. Mitchell and N. Traficante and J. Hendley and H. Thorne and M. Shackleton and D.K. Miller and G.M. Arnau and R.W. Tothill and T.P. Holloway and T. Semple and I. Harliwong and C. Nourse and E. Nourbakhsh and S. Manning and S. Idrisoglu and T.J.C. Bruxner and A.N. Christ and B. Poudel and O. Holmes and M. Anderson and C. Leonard and A. Lonie and N. Hall and S. Wood and D.F. Taylor and Q. Xu and {Lynn Fink}, J. and N. Waddell and R. Drapkin and E. Stronach and H. Gabra and R. Brown and A. Jewell and S.H. Nagaraj and E. Markham and P.J. Wilson and J. Ellul and O. Mcnally and M.A. Doyle and R. Vedururu and Colin Stewart and Yee Leung and E. Lengyel and A. Defazio and J.V. Pearson and S.M. Grimmond",
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    Patch, AM, Christie, EL, Etemadmoghadam, D, Garsed, DW, George, J, Fereday, S, Nones, K, Cowin, P, Alsop, K, Bailey, PJ, Kassahn, KS, Newell, F, Quinn, MCJ, Kazakoff, S, Quek, K, Wilhelm-Benartzi, C, Curry, E, Leong, HS, Hamilton, A, Mileshkin, L, Au-Yeung, G, Kennedy, C, Hung, J, Chiew, YE, Harnett, P, Friedlander, M, Quinn, M, Pyman, J, Cordner, S, O'Brien, P, Leditschke, J, Young, G, Strachan, K, Waring, P, Azar, W, Mitchell, C, Traficante, N, Hendley, J, Thorne, H, Shackleton, M, Miller, DK, Arnau, GM, Tothill, RW, Holloway, TP, Semple, T, Harliwong, I, Nourse, C, Nourbakhsh, E, Manning, S, Idrisoglu, S, Bruxner, TJC, Christ, AN, Poudel, B, Holmes, O, Anderson, M, Leonard, C, Lonie, A, Hall, N, Wood, S, Taylor, DF, Xu, Q, Lynn Fink, J, Waddell, N, Drapkin, R, Stronach, E, Gabra, H, Brown, R, Jewell, A, Nagaraj, SH, Markham, E, Wilson, PJ, Ellul, J, Mcnally, O, Doyle, MA, Vedururu, R, Stewart, C, Leung, Y, Lengyel, E, Defazio, A, Pearson, JV & Grimmond, SM 2015, 'Whole-genome characterization of chemoresistant ovarian cancer' Nature, vol. 521, no. 7553, pp. 489-494. https://doi.org/10.1038/nature14410

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

    In: Nature, Vol. 521, No. 7553, 2015, p. 489-494.

    Research output: Contribution to journalArticle

    TY - JOUR

    T1 - Whole-genome characterization of chemoresistant ovarian cancer

    AU - Patch, A.M.

    AU - Christie, E.L.

    AU - Etemadmoghadam, D.

    AU - Garsed, D.W.

    AU - George, J.

    AU - Fereday, S.

    AU - Nones, K.

    AU - Cowin, P.

    AU - Alsop, K.

    AU - Bailey, P.J.

    AU - Kassahn, K.S.

    AU - Newell, F.

    AU - Quinn, M.C.J.

    AU - Kazakoff, S.

    AU - Quek, K.

    AU - Wilhelm-Benartzi, C.

    AU - Curry, E.

    AU - Leong, H.S.

    AU - Hamilton, A.

    AU - Mileshkin, L.

    AU - Au-Yeung, G.

    AU - Kennedy, C.

    AU - Hung, J.

    AU - Chiew, Y.E.

    AU - Harnett, P.

    AU - Friedlander, M.

    AU - Quinn, M.

    AU - Pyman, J.

    AU - Cordner, S.

    AU - O'Brien, P.

    AU - Leditschke, J.

    AU - Young, G.

    AU - Strachan, K.

    AU - Waring, P.

    AU - Azar, W.

    AU - Mitchell, C.

    AU - Traficante, N.

    AU - Hendley, J.

    AU - Thorne, H.

    AU - Shackleton, M.

    AU - Miller, D.K.

    AU - Arnau, G.M.

    AU - Tothill, R.W.

    AU - Holloway, T.P.

    AU - Semple, T.

    AU - Harliwong, I.

    AU - Nourse, C.

    AU - Nourbakhsh, E.

    AU - Manning, S.

    AU - Idrisoglu, S.

    AU - Bruxner, T.J.C.

    AU - Christ, A.N.

    AU - Poudel, B.

    AU - Holmes, O.

    AU - Anderson, M.

    AU - Leonard, C.

    AU - Lonie, A.

    AU - Hall, N.

    AU - Wood, S.

    AU - Taylor, D.F.

    AU - Xu, Q.

    AU - Lynn Fink, J.

    AU - Waddell, N.

    AU - Drapkin, R.

    AU - Stronach, E.

    AU - Gabra, H.

    AU - Brown, R.

    AU - Jewell, A.

    AU - Nagaraj, S.H.

    AU - Markham, E.

    AU - Wilson, P.J.

    AU - Ellul, J.

    AU - Mcnally, O.

    AU - Doyle, M.A.

    AU - Vedururu, R.

    AU - Stewart, Colin

    AU - Leung, Yee

    AU - Lengyel, E.

    AU - Defazio, A.

    AU - Pearson, J.V.

    AU - Grimmond, S.M.

    PY - 2015

    Y1 - 2015

    N2 - © 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.

    AB - © 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.

    U2 - 10.1038/nature14410

    DO - 10.1038/nature14410

    M3 - Article

    VL - 521

    SP - 489

    EP - 494

    JO - Nature

    JF - Nature

    SN - 0028-0836

    IS - 7553

    ER -

    Patch AM, Christie EL, Etemadmoghadam D, Garsed DW, George J, Fereday S et al. Whole-genome characterization of chemoresistant ovarian cancer. Nature. 2015;521(7553):489-494. https://doi.org/10.1038/nature14410