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; 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

doi:10.1038/nature14410

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

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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 language	English
Pages (from-to)	489-494
Journal	Nature
Volume	521
Issue number	7553
DOIs	https://doi.org/10.1038/nature14410
Publication status	Published - 2015

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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., ... Grimmond, S. M. (2015). Whole-genome characterization of chemoresistant ovarian cancer. Nature, 521(7553), 489-494. https://doi.org/10.1038/nature14410

@article{4655fa132fb24534b2fc5160dbb02466,

title = "Whole-genome characterization of chemoresistant ovarian cancer",

abstract = "{\textcopyright} 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",

year = "2015",

doi = "10.1038/nature14410",

language = "English",

volume = "521",

pages = "489--494",

journal = "Nature",

issn = "0028-0836",

publisher = "Nature Publishing Group - Macmillan Publishers",

number = "7553",

}

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

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

SN - 0028-0836

VL - 521

SP - 489

EP - 494

JO - Nature

JF - Nature

IS - 7553

ER -

Whole-genome characterization of chemoresistant ovarian cancer

Abstract

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