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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.

Type Journal
ISBN 2041-1723 (Electronic) 2041-1723 (Linking)
Authors Stirzaker, C.; Zotenko, E.; Song, J. Z.; Qu, W.; Nair, S. S.; Locke, W. J.; Stone, A.; Armstong, N. J.; Robinson, M. D.; Dobrovic, A.; Avery-Kiejda, K. A.; Peters, K. M.; French, J. D.; Stein, S.; Korbie, D. J.; Trau, M.; Forbes, J. F.; Scott, R. J.; Brown, M. A.; Francis, G. D.; Clark, S. J.;
Publisher Name Nature Communications
Published Date 2015-01-01
Published Volume 6
Published Pages 5899
Status Published in-print
URL link to publisher's version http://www.ncbi.nlm.nih.gov/pubmed/25641231
OpenAccess link to author's accepted manuscript version https://publications.gimr.garvan.org.au/open-access/12898