Whole-genome characterization of chemoresistant ovarian cancer

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

doi:10.1038/nature14410

Whole-genome characterization of chemoresistant ovarian cancer

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Pages (from-to)	489-494
Number of pages	6
Journal	Nature
Volume	521
Issue number	7553
DOIs	https://doi.org/10.1038/nature14410
Publication status	Published - 28 May 2015
Externally published	Yes

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10.1038/nature14410

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

@article{95bd66bfcc6244d3a3b2d3706f3fc10c,

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.",

author = "Patch, {Ann Marie} and Christie, {Elizabeth L.} and Dariush Etemadmoghadam and Garsed, {Dale W.} and Joshy George and Sian Fereday and Katia Nones and Prue Cowin and Kathryn Alsop and Bailey, {Peter J.} and Kassahn, {Karin S.} and Felicity Newell and Quinn, {Michael C.J.} and Stephen Kazakoff and Kelly Quek and Charlotte Wilhelm-Benartzi and Ed Curry and Leong, {Huei San} and Anne Hamilton and Linda Mileshkin and George Au-Yeung and Catherine Kennedy and Jillian Hung and Chiew, {Yoke Eng} and Paul Harnett and Michael Friedlander and Michael Quinn and Jan Pyman and Stephen Cordner and Patricia O'Brien and Jodie Leditschke and Greg Young and Kate Strachan and Paul Waring and Walid Azar and Chris Mitchell and Nadia Traficante and Joy Hendley and Heather Thorne and Mark Shackleton and Miller, {David K.} and Arnau, {Gisela Mir} and Tothill, {Richard W.} and Holloway, {Timothy P.} and Timothy Semple and Ivon Harliwong and Craig Nourse and Ehsan Nourbakhsh and Suzanne Manning and Senel Idrisoglu and Bruxner, {Timothy J.C.} and Christ, {Angelika N.} and Barsha Poudel and Oliver Holmes and Matthew Anderson and Conrad Leonard and Andrew Lonie and Nathan Hall and Scott Wood and Taylor, {Darrin F.} and Qinying Xu and {Lynn Fink}, J. and Nick Waddell and Ronny Drapkin and Euan Stronach and Hani Gabra and Robert Brown and Andrea Jewell and Nagaraj, {Shivashankar H.} and Emma Markham and Wilson, {Peter J.} and Jason Ellul and Orla McNally and Doyle, {Maria A.} and Ravikiran Vedururu and Collin Stewart and Ernst Lengyel and Pearson, {John V.} and Nicola Waddell and Anna Defazio and Grimmond, {Sean M.} and Bowtell, {David D.L.}",

year = "2015",

month = may,

day = "28",

doi = "10.1038/nature14410",

language = "English",

volume = "521",

pages = "489--494",

journal = "Nature",

issn = "0028-0836",

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, Lengyel, E, Pearson, JV, Waddell, N, Defazio, A, Grimmond, SM & Bowtell, DDL 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, Ann Marie

AU - Christie, Elizabeth L.

AU - Etemadmoghadam, Dariush

AU - Garsed, Dale W.

AU - George, Joshy

AU - Fereday, Sian

AU - Nones, Katia

AU - Cowin, Prue

AU - Alsop, Kathryn

AU - Bailey, Peter J.

AU - Kassahn, Karin S.

AU - Newell, Felicity

AU - Quinn, Michael C.J.

AU - Kazakoff, Stephen

AU - Quek, Kelly

AU - Wilhelm-Benartzi, Charlotte

AU - Curry, Ed

AU - Leong, Huei San

AU - Hamilton, Anne

AU - Mileshkin, Linda

AU - Au-Yeung, George

AU - Kennedy, Catherine

AU - Hung, Jillian

AU - Chiew, Yoke Eng

AU - Harnett, Paul

AU - Friedlander, Michael

AU - Quinn, Michael

AU - Pyman, Jan

AU - Cordner, Stephen

AU - O'Brien, Patricia

AU - Leditschke, Jodie

AU - Young, Greg

AU - Strachan, Kate

AU - Waring, Paul

AU - Azar, Walid

AU - Mitchell, Chris

AU - Traficante, Nadia

AU - Hendley, Joy

AU - Thorne, Heather

AU - Shackleton, Mark

AU - Miller, David K.

AU - Arnau, Gisela Mir

AU - Tothill, Richard W.

AU - Holloway, Timothy P.

AU - Semple, Timothy

AU - Harliwong, Ivon

AU - Nourse, Craig

AU - Nourbakhsh, Ehsan

AU - Manning, Suzanne

AU - Idrisoglu, Senel

AU - Bruxner, Timothy J.C.

AU - Christ, Angelika N.

AU - Poudel, Barsha

AU - Holmes, Oliver

AU - Anderson, Matthew

AU - Leonard, Conrad

AU - Lonie, Andrew

AU - Hall, Nathan

AU - Wood, Scott

AU - Taylor, Darrin F.

AU - Xu, Qinying

AU - Lynn Fink, J.

AU - Waddell, Nick

AU - Drapkin, Ronny

AU - Stronach, Euan

AU - Gabra, Hani

AU - Brown, Robert

AU - Jewell, Andrea

AU - Nagaraj, Shivashankar H.

AU - Markham, Emma

AU - Wilson, Peter J.

AU - Ellul, Jason

AU - McNally, Orla

AU - Doyle, Maria A.

AU - Vedururu, Ravikiran

AU - Stewart, Collin

AU - Lengyel, Ernst

AU - Pearson, John V.

AU - Waddell, Nicola

AU - Defazio, Anna

AU - Grimmond, Sean M.

AU - Bowtell, David D.L.

PY - 2015/5/28

Y1 - 2015/5/28

N2 - 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 - 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.

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U2 - 10.1038/nature14410

DO - 10.1038/nature14410

M3 - Article

C2 - 26017449

AN - SCOPUS:84930638395

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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