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 and Susan J. Clark ()
Additional contact information
Clare Stirzaker: Epigenetics Group, Garvan Institute of Medical Research
Elena Zotenko: Epigenetics Group, Garvan Institute of Medical Research
Jenny Z. Song: Epigenetics Group, Garvan Institute of Medical Research
Wenjia Qu: Epigenetics Group, Garvan Institute of Medical Research
Shalima S. Nair: Epigenetics Group, Garvan Institute of Medical Research
Warwick J. Locke: Epigenetics Group, Garvan Institute of Medical Research
Andrew Stone: Epigenetics Group, Garvan Institute of Medical Research
Nicola J. Armstong: Epigenetics Group, Garvan Institute of Medical Research
Mark D. Robinson: Epigenetics Group, Garvan Institute of Medical Research
Alexander Dobrovic: Translational Genomics & Epigenomics Laboratory, Olivia Newton-John Cancer Research Institute
Kelly A. Avery-Kiejda: School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle
Kate M. Peters: School of Chemistry and Molecular Biosciences, University of Queensland
Juliet D. French: School of Chemistry and Molecular Biosciences, University of Queensland
Sandra Stein: Pathology Queensland, Princess Alexandra Hospital
Darren J. Korbie: Australian Institute for Bioengineering and Nanotechnology, University of Queensland
Matt Trau: School of Chemistry and Molecular Biosciences, University of Queensland
John F. Forbes: School of Medicine and Public Health, Faculty of Health and Medicine, University of Newcastle
Rodney J. Scott: School of Biomedical Sciences and Pharmacy, Faculty of Health, University of Newcastle
Melissa A. Brown: School of Chemistry and Molecular Biosciences, University of Queensland
Glenn D. Francis: Pathology Queensland, Princess Alexandra Hospital
Susan J. Clark: Epigenetics Group, Garvan Institute of Medical Research

Nature Communications, 2015, vol. 6, issue 1, 1-11

Abstract: 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.

Date: 2015
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DOI: 10.1038/ncomms6899

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