Fig. 1

Identification of seven DNA methylation epitypes in breast cancer. a DNA methylation epitypes in the discovery cohort based on bootstrap clustering of 2108 CpG sites with breast cancer–specific methylation levels. The heat map displays β values (rows) ranging from unmethylated (blue) to methylated (yellow) for three sample groups (columns) comprising 188 breast tumors divided into 7 epitypes by bootstrap clustering, 96 normal breast tissues from The Cancer Genome Atlas, and 4 normal cell types (HMEC human mammary epithelial cells, HMF human mammary fibroblasts, HMEndoC human mammary endothelial cells, Blood blood leukocytes). Sample annotations at the bottom display estrogen receptor status, gene expression subtypes, germline mutations in BRCA1 and BRCA2 (black = yes, white = no, gray = NA). CpG tracks on the left side: GEX correlation between DNA methylation and gene expression levels across the validation cohort (red = positive correlation, green = negative correlation, gray = low correlation, white = no associated gene); HMEC-Chrom and H1hESC-Chrom chromatin states in human mammary epithelial cells and H1 human embryonic stem cells, respectively (red = active promoter, purple = poised promoter, gray = Polycomb-repressed, yellow = enhancer, green = transcribed, blue = insulator, white = heterochromatin); HMEC-EZH2 EZH2 targets in human mammary epithelial cells; HMEC-DNASE accessible DNA in human mammary epithelial cells (black = yes, white = no); CpG island track (black = island, gray = shore/shelf, white = open sea). CpG track on the right side: Group CpG sites with epitype-specific methylation patterns (red = methylated in ET7, light blue = methylated in ET5, green = demethylated in ET4, blue = demethylated in luminal epitypes, orange = demethylated in ET7). b Global hypermethylation scores for all CpG sites (left) and all CpG sites in promoters and CpG islands (right) across the epitypes. c Proliferative rates of tumors across the epitypes. In (b) and (c), the number of tumors in each epitype is shown at the top. ER estrogen receptor, HER2 human epidermal growth factor receptor 2