Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

Clare Stirzaker; Elena Zotenko; Jenny Z Song; Wenjia Qu; Shalima S Nair; Warwick J Locke; Andrew Stone; Nicola J Armstong; Mark D Robinson; Alexander Dobrovic; Kelly A Avery-Kiejda; Kate M Peters; Juliet D French; Sandra Stein; Darren J Korbie; Matt Trau; John F Forbes; Rodney J Scott; Melissa A Brown; Glenn D Francis; Susan J Clark

doi:10.1038/ncomms6899

Methylome sequencing in triple-negative breast cancer reveals distinct methylation clusters with prognostic value

Nat Commun. 2015 Feb 2:6:5899. doi: 10.1038/ncomms6899.

Authors

Clare Stirzaker¹, Elena Zotenko¹, Jenny Z Song², Wenjia Qu², Shalima S Nair¹, Warwick J Locke¹, Andrew Stone¹, Nicola J Armstong³, Mark D Robinson⁴, Alexander Dobrovic⁵, Kelly A Avery-Kiejda⁶, Kate M Peters⁷, Juliet D French⁸, Sandra Stein⁹, Darren J Korbie¹⁰, Matt Trau¹¹, John F Forbes¹², Rodney J Scott¹³, Melissa A Brown⁷, Glenn D Francis¹⁴, Susan J Clark¹

Affiliations

¹ 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.
² Epigenetics Group, Cancer Division, Garvan Institute of Medical Research, Sydney, New South Wales 2010, Australia.
³ 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.
⁴ 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.
⁵ Translational Genomics &Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute, Melbourne, Victoria 3084, Australia.
⁶ School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle, Newcastle, New South Wales 2308, Australia.
⁷ School of Chemistry and Molecular Biosciences, University of Queensland, Brisbane, Queensland 4072, Australia.
⁸ 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.
⁹ Pathology Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia.
¹⁰ Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia.
¹¹ 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.
¹² School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle, Newcastle, New South Wales 2305, Australia.
¹³ 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.
¹⁴ 1] Pathology Queensland, Princess Alexandra Hospital, Brisbane, Queensland 4102, Australia [2] Australian Institute for Bioengineering and Nanotechnology, University of Queensland, Brisbane, Queensland 4072, Australia.

PMID: 25641231
DOI: 10.1038/ncomms6899

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

DNA Methylation / genetics
DNA Methylation / physiology*
Epigenomics
Female
Humans
Molecular Sequence Data
Prognosis
Triple Negative Breast Neoplasms / genetics*
Triple Negative Breast Neoplasms / pathology*

Associated data

GENBANK/GSE58020