Whole genome characterisation of chemoresistant ovarian cancer [Illumina_450K_Methylation]
Ontology highlight
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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