title: An integrated genomics analysis of epigenetic subtypes in human breast tumors links DNA methylation patterns to chromatin states in normal mammary cells.
abstract: BACKGROUND
  Aberrant DNA methylation is frequently observed in breast cancer. However, the relationship between methylation patterns and the heterogeneity of breast cancer has not been comprehensively characterized.
  
  
  METHODS
  Whole-genome DNA methylation analysis using Illumina Infinium HumanMethylation450 BeadChip arrays was performed on 188 human breast tumors. Unsupervised bootstrap consensus clustering was performed to identify DNA methylation epigenetic subgroups (epitypes). The Cancer Genome Atlas data, including methylation profiles of 669 human breast tumors, was used for validation. The identified epitypes were characterized by integration with publicly available genome-wide data, including gene expression levels, DNA copy numbers, whole-exome sequencing data, and chromatin states.
  
  
  RESULTS
  We identified seven breast cancer epitypes. One epitype was distinctly associated with basal-like tumors and with BRCA1 mutations, one epitype contained a subset of ERBB2-amplified tumors characterized by multiple additional amplifications and the most complex genomes, and one epitype displayed a methylation profile similar to normal epithelial cells. Luminal tumors were stratified into the remaining four epitypes, with differences in promoter hypermethylation, global hypomethylation, proliferative rates, and genomic instability. Specific hyper- and hypomethylation across the basal-like epitype was rare. However, we observed that the candidate genomic instability drivers BRCA1 and HORMAD1 displayed aberrant methylation linked to gene expression levels in some basal-like tumors. Hypomethylation in luminal tumors was associated with DNA repeats and subtelomeric regions. We observed two dominant patterns of aberrant methylation in breast cancer. One pattern, constitutively methylated in both basal-like and luminal breast cancer, was linked to genes with promoters in a Polycomb-repressed state in normal epithelial cells and displayed no correlation with gene expression levels. The second pattern correlated with gene expression levels and was associated with methylation in luminal tumors and genes with active promoters in normal epithelial cells.
  
  
  CONCLUSIONS
  Our results suggest that hypermethylation patterns across basal-like breast cancer may have limited influence on tumor progression and instead reflect the repressed chromatin state of the tissue of origin. On the contrary, hypermethylation patterns specific to luminal breast cancer influence gene expression, may contribute to tumor progression, and may present an actionable epigenetic alteration in a subset of luminal breast cancers.
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. karolina.holm@med.lu.se.|CREATE Health Centre for Translational Cancer Research, Lund University, Lund, Sweden. karolina.holm@med.lu.se.
authors.forename: Karolina
authors.initials: K
authors.lastname: Holm
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. johan.staaf@med.lu.se.|CREATE Health Centre for Translational Cancer Research, Lund University, Lund, Sweden. johan.staaf@med.lu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Staaf
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. martin.lauss@med.lu.se.|CREATE Health Centre for Translational Cancer Research, Lund University, Lund, Sweden. martin.lauss@med.lu.se.
authors.forename: Martin
authors.initials: M
authors.lastname: Lauss
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. mattias.aine@med.lu.se.
authors.forename: Mattias
authors.initials: M
authors.lastname: Aine
authors.affiliation: Division of Translational Cancer Research, Department of Laboratory Medicine Lund, Lund University, Lund, Sweden. david.lindgren@med.lu.se.
authors.forename: David
authors.initials: D
authors.lastname: Lindgren
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. par-ola.bendahl@med.lu.se.
authors.forename: Pär-Ola
authors.initials: PO
authors.lastname: Bendahl
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. johan.vallon-christersson@med.lu.se.|CREATE Health Centre for Translational Cancer Research, Lund University, Lund, Sweden. johan.vallon-christersson@med.lu.se.
authors.forename: Johan
authors.initials: J
authors.lastname: Vallon-Christersson
authors.affiliation: Department of Pathology, Landspitali-University Hospital, Reykjavik, Iceland. rosa@landspitali.is.
authors.forename: Rosa Bjork
authors.initials: RB
authors.lastname: Barkardottir
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. mattias.hoglund@med.lu.se.
authors.forename: Mattias
authors.initials: M
authors.lastname: Höglund
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. ake.borg@med.lu.se.|CREATE Health Centre for Translational Cancer Research, Lund University, Lund, Sweden. ake.borg@med.lu.se.
authors.forename: Åke
authors.initials: Å
authors.lastname: Borg
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. goran_b.jonsson@med.lu.se.|CREATE Health Centre for Translational Cancer Research, Lund University, Lund, Sweden. goran_b.jonsson@med.lu.se.
authors.forename: Göran
authors.initials: G
authors.lastname: Jönsson
authors.affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden. markus.ringner@med.lu.se.|CREATE Health Centre for Translational Cancer Research, Lund University, Lund, Sweden. markus.ringner@med.lu.se.
authors.forename: Markus
authors.initials: M
authors.lastname: Ringnér
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002843:Chromatin / Q000235:genetics*; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D044127:Epigenesis, Genetic / Q000235:genetics*; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D015894:Genome, Human; D006801:Humans; D042361:Mammary Glands, Human / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics; D020411:Oligonucleotide Array Sequence Analysis / Q000379:methods; D011401:Promoter Regions, Genetic
chemical_list: D002843:Chromatin; D009363:Neoplasm Proteins