Whole-genome characterization of chemoresistant ovarian cancer.

Nature ·第 521 卷 ·第 7553 期 ·2015-06-29

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

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.

文献信息

期刊

Nature

期刊简称

Nature

ISSN

0028-0836

DOI

10.1038/nature14410

发表日期

2015-06-29

收录日期

2015-05-28

更新日期

2016-11-25

语言

英语

国家/地区

England

NLM ID

0410462

外部链接

PubMed 原文 DOI: 10.1038/nature14410 查看期刊详情

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Whole-genome characterization of chemoresistant ovarian cancer.

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