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DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer

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  • Andrew E Teschendorff

    (University College London
    CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences
    Statistical Cancer Genomics, Paul O’Gorman Building, UCL Cancer Institute, University College London)

  • Yang Gao

    (CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences)

  • Allison Jones

    (University College London)

  • Matthias Ruebner

    (University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nuremberg)

  • Matthias W. Beckmann

    (University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nuremberg)

  • David L. Wachter

    (Institute of Pathology, University Clinic Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg)

  • Peter A. Fasching

    (University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nuremberg)

  • Martin Widschwendter

    (University College London)

Abstract

Identifying molecular alterations in normal tissue adjacent to cancer is important for understanding cancer aetiology and designing preventive measures. Here we analyse the DNA methylome of 569 breast tissue samples, including 50 from cancer-free women and 84 from matched normal cancer pairs. We use statistical algorithms for dissecting intra- and inter-sample cellular heterogeneity and demonstrate that normal tissue adjacent to breast cancer is characterized by tens to thousands of epigenetic alterations. We show that their genomic distribution is non-random, being strongly enriched for binding sites of transcription factors specifying chromatin architecture. We validate the field defects in an independent cohort and demonstrate that over 30% of the alterations exhibit increased enrichment within matched cancer samples. Breast cancers highly enriched for epigenetic field defects, exhibit adverse clinical outcome. Our data support a model where clonal epigenetic reprogramming towards reduced differentiation in normal tissue is an important step in breast carcinogenesis.

Suggested Citation

  • Andrew E Teschendorff & Yang Gao & Allison Jones & Matthias Ruebner & Matthias W. Beckmann & David L. Wachter & Peter A. Fasching & Martin Widschwendter, 2016. "DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer," Nature Communications, Nature, vol. 7(1), pages 1-12, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10478
    DOI: 10.1038/ncomms10478
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    Cited by:

    1. Tianyu Zhu & Huige Tong & Zhaozhen Du & Stephan Beck & Andrew E. Teschendorff, 2024. "An improved epigenetic counter to track mitotic age in normal and precancerous tissues," Nature Communications, Nature, vol. 15(1), pages 1-19, December.

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