title: Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value.
abstract: Epigenetic alterations in the cancer methylome are common in breast cancer and provide novel options for tumour stratification. Here, we perform whole-genome methylation capture sequencing on small amounts of DNA isolated from formalin-fixed, paraffin-embedded tissue from triple-negative breast cancer (TNBC) and matched normal samples. We identify differentially methylated regions (DMRs) enriched with promoters associated with transcription factor binding sites and DNA hypersensitive sites. Importantly, we stratify TNBCs into three distinct methylation clusters associated with better or worse prognosis and identify 17 DMRs that show a strong association with overall survival, including DMRs located in the Wilms tumour 1 (WT1) gene, bi-directional-promoter and antisense WT1-AS. Our data reveal that coordinated hypermethylation can occur in oestrogen receptor-negative disease, and that characterizing the epigenetic framework provides a potential signature to stratify TNBCs. Together, our findings demonstrate the feasibility of profiling the cancer methylome with limited archival tissue to identify regulatory regions associated with cancer.
authors: 1] Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors: Clare
authors: C
authors: Stirzaker
authors: 1] Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors: Elena
authors: E
authors: Zotenko
authors: Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors: Jenny Z
authors: JZ
authors: Song
authors: Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
authors: Wenjia
authors: W
authors: Qu
authors: 1] Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors: Shalima S
authors: SS
authors: Nair
authors: 1] Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors: Warwick J
authors: WJ
authors: Locke
authors: 1] Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors: Andrew
authors: A
authors: Stone
authors: 1] Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] School of Mathematics and Statistics, University of Sydney, Sydney, New South Wales 2006, Australia.
authors: Nicola J
authors: NJ
authors: Armstong
authors: 1] Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] Swiss Institute of Bioinformatics and Institute of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
authors: Mark D
authors: MD
authors: Robinson
authors: Translational Genomics &Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Victoria 3084, Australia.
authors: Alexander
authors: A
authors: Dobrovic
authors: School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, New South Wales 2308, Australia.
authors: Kelly A
authors: KA
authors: Avery-Kiejda
authors: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.
authors: Kate M
authors: KM
authors: Peters
authors: 1] School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia [2] Department of Genetics and Computational Biology, QIMR Berghofer Medical Research Institute, Brisbane, Queensland 4029, Australia.
authors: Juliet D
authors: JD
authors: French
authors: Pathology Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
authors: Sandra
authors: S
authors: Stein
authors: Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia.
authors: Darren J
authors: DJ
authors: Korbie
authors: 1] School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia [2] Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia.
authors: Matt
authors: M
authors: Trau
authors: School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales 2305, Australia.
authors: John F
authors: JF
authors: Forbes
authors: 1] School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, New South Wales 2308, Australia [2] Division of Molecular Medicine, Hunter Area Pathology Service and the Hunter Medical Research Institute, John Hunter Hospital, Newcastle, New South Wales 2305, Australia.
authors: Rodney J
authors: RJ
authors: Scott
authors: School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.
authors: Melissa A
authors: MA
authors: Brown
authors: 1] Pathology Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia [2] Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia.
authors: Glenn D
authors: GD
authors: Francis
authors: 1] Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia [2] St Vincent's Clinical School, University of NSW, Sydney, New South Wales 2010, Australia.
authors: Susan J
authors: SJ
authors: Clark
mesh_terms: D019175:DNA Methylation / Q000235:genetics / Q000502:physiology*; D057890:Epigenomics; D005260:Female; D006801:Humans; D008969:Molecular Sequence Data; D011379:Prognosis; D064726:Triple Negative Breast Neoplasms / Q000235:genetics* / Q000473:pathology*