Transcriptomics

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Whole genome characterisation of chemoresistant ovarian cancer [Illumina_450K_Methylation]


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. Genomic DNA (500ng) was bisulfite converted using EZ DNA methylation Kit (Zimo Research) following the manufacturer’s protocol with modification for Illumina Infinium Methyaltion arrays. Samples were hybridized to Infinium Human Methylation 450K BeadChips (Illumina) according to the manufacturer’s protocol. Arrays were scanned on Iscan (Illumina). Data was background corrected, normalized to internal controls and QC was performed at the probe and sample level. COMBAT was used to remove batch effects (Johnson et al., 2007). Contributor: The Australian Ovarian Cancer Study Group

ORGANISM(S): Homo sapiens  

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

PROVIDER: E-GEOD-65820 | ArrayExpress | 2015-05-19

SECONDARY ACCESSION(S): GSE65820PRJNA275137

REPOSITORIES: GEO, ArrayExpress

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