title: DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer.
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.
authors.affiliation: Department of Women's Cancer, University College London, Medical School Building, Room 340, 74 Huntley Street, London WC1E 6AU, UK.|CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.|Statistical Cancer Genomics, Paul O'Gorman Building, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK.
authors.forename: Andrew E
authors.initials: AE
authors.lastname: Teschendorff
authors.affiliation: CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai 200031, China.
authors.forename: Yang
authors.initials: Y
authors.lastname: Gao
authors.affiliation: Department of Women's Cancer, University College London, Medical School Building, Room 340, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Allison
authors.initials: A
authors.lastname: Jones
authors.affiliation: Department of Gynaecology and Obstetrics, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Ruebner
authors.affiliation: Department of Gynaecology and Obstetrics, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Matthias W
authors.initials: MW
authors.lastname: Beckmann
authors.affiliation: Department of Surgical Pathology, Institute of Pathology, University Clinic Erlangen, Friedrich-Alexander-University Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: David L
authors.initials: DL
authors.lastname: Wachter
authors.affiliation: Department of Gynaecology and Obstetrics, University Clinic Erlangen, Friedrich-Alexander University Erlangen-Nuremberg, Erlangen 91054, Germany.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Fasching
authors.affiliation: Department of Women's Cancer, University College London, Medical School Building, Room 340, 74 Huntley Street, London WC1E 6AU, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Widschwendter
mesh_terms: D000328:Adult; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D019175:DNA Methylation; D057890:Epigenomics; D005260:Female; D053263:Gene Regulatory Networks; D006801:Humans
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