Whole-genome characterization of chemoresistant ovarian cancer.

Nature 2015 May;521(7553):489-94

1] Peter MacCallum Cancer Centre, East Melbourne, Victoria 3002, Australia [2] Department of Pathology, University of Melbourne, Parkville, Victoria 3052, Australia [3] Sir Peter MacCallum Cancer Centre Department of Oncology, University of Melbourne, Parkville, Victoria 3052, Australia [4] Ovarian Cancer Action Research Centre, Department of Surgery and Cancer, Imperial College London, London W12 0HS, UK [5] Department of Biochemistry and Molecular Biology, University of Melbourne, Parkville, Victoria 3052, Australia.

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.

Download full-text PDF

Source
http://dx.doi.org/10.1038/nature14410DOI Listing
May 2015
169 Reads
193 Citations
42.351 Impact Factor

Publication Analysis

Top Keywords

ovarian cancer
8
chemotherapy resistance
4
resistance ccne1
4
acquired chemotherapy
4
contributes acquired
4
pten hgsc
4
hgsc contributes
4
ccne1 amplification
4
amplification common
4
refractory disease
4
disease observed
4
resistant refractory
4
primary resistant
4
rad51b pten
4
common primary
4
observed molecular
4
nf1 rad51b
4
acquired resistant
4
resistant disease
4
matched acquired
4

Similar Publications