Whole-genome characterization of chemoresistant ovarian cancer.
Document Type
Article
Publication Date
5-28-2015
JAX Source
Nature 2015 May 28; 521(7553):489-94.
Volume
521
Issue
7553
First Page
489
Last Page
494
ISSN
1476-4687
PMID
26017449
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. Nature 2015 May 28; 521(7553):489-94.
Recommended Citation
Patch A,
Christie E,
Etemadmoghadam D,
Garsed D,
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Nones K,
Cowin P,
Alsop K,
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Newell F,
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Wilhelm-Benartzi C,
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Leong H,
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Mileshkin L,
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Hendley J,
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Grimmond S,
Bowtell D.
Whole-genome characterization of chemoresistant ovarian cancer. Nature 2015 May 28; 521(7553):489-94.