On Advanced Fellowship, NAF project number 522438 and award number 164914. The research AZD-8055 site leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007-2013) under grant agreement number 305428 (Project EpiFemCare) and was strongly supported by funds from The Eve Appeal (http://www.eveappeal.org.uk/) and undertaken at UCLH/UCL, which received a proportion of its funding from the Department of Health NIHR Biomedical Research Centers funding scheme. Author details 1 CAS Key Lab of Computational Biology, CAS-MPG Partner Institute for Computational Biology, Shanghai Institute for Biological Sciences, Chinese Academy of Sciences, Shanghai, China. 2Statistical Cancer Genomics, Paul O’Gorman Building, UCL Cancer Institute, University College London, 72 Huntley Street, London WC1E 6BT, UK. 3Department of Women’s Cancer, University College London, 74 Huntley Street, London WC1E 6AU, UK. Received: 19 December 2015 Accepted: 16 AprilConclusions In summary, we have here demonstrated that DNA methylation outliers in pre-neoplastic lesions define epigenetic field defects, marking cells which become enriched in invasive disease and which may therefore contribute casually to cancer progression. We recommend that studies aiming to identify epigenetic field defects in pre-neoplastic cells, and which for cost or logistical reasons may be underpowered, make use of DV algorithms like iEVORA, which improve the sensitivity, since this may be preferable over using algorithms which only provide strong control of the type-1 error rate and which therefore lack sensitivity. Ethical statement All data analysed in this study is in the public domain and have been analysed in previous studies. Additional filesAdditional file 1: Document containing all Supplementary Figures and Tables. (PDF 925 kb) Additional file 2: GSEA result tables of hypervariable DVCs, as identified using iEVORA, in the normal breast study comparing normal breast from healthy women to normal breast adjacent to breast cancer. There are 4 tables, corresponding to hypervariable DVCs mapping to TSS1500, TSS200 or 1st Exon regions, and which are hypermethylated (dvUPdmUP) or hypomethylated (dvUPdmDN) in normal-adjacent tissue, as well as hypervariable DVCs mapping to gene-body or 5UTR regions, which areReferences 1. Perou PubMed ID:https://www.ncbi.nlm.nih.gov/pubmed/28128382 CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA, et al. Molecular portraits of human breast tumours. Nature. 2000;406:747?2. 2. Alizadeh A, Eisen M, Davis RE, Ma C, Sabet H, Tran T, Powell JI, Yang L, Marti GE, Moore DT, et al. The lymphochip: a specialized cDNA microarray for the genomic-scale analysis of gene expression in normal and malignant lymphocytes. Cold Spring Harb Symp Quant Biol. 1999;64:71?. 3. Pollack JR, Perou CM, Alizadeh AA, Eisen MB, Pergamenschikov A, Williams CF, Jeffrey SS, Botstein D, Brown PO. Genome-wide analysis of DNA copynumber changes using cDNA microarrays. Nat Genet. 1999;23:41?. 4. Tusher VG, Tibshirani R, Chu G. Significance analysis of microarrays applied to the ionizing radiation response. Proc Natl Acad Sci U S A. 2001;98:5116?1. 5. Smyth GK. Linear models and empirical bayes methods for assessing differential expression in microarray experiments. Stat Appl Genet Mol Biol. 2004;3:Article3. 6. Wettenhall JM, Smyth GK. limmaGUI: a graphical user interface for linear modeling of microarray data. Bioinformatics. 2004;20:3705?. 7. Wilcoxon F. Individual co.