title: Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma.
abstract: BACKGROUND
  Urothelial carcinoma of the bladder (UC) is a common malignancy. Although extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. Multi-level genomic data may be used to profile the regulatory potential and landscape of differential methylation in cancer and gain understanding of the processes underlying epigenetic and phenotypic characteristics of tumors.
  
  
  METHODS
  We perform genome-wide DNA methylation profiling of 98 gene-expression subtyped tumors to identify between-tumor differentially methylated regions (DMRs). We integrate multi-level publically available genomic data generated by the ENCODE consortium to characterize the regulatory potential of UC DMRs.
  
  
  RESULTS
  We identify 5,453 between-tumor DMRs and derive four DNA methylation subgroups of UC with distinct associations to clinicopathological features and gene expression subtypes. We characterize three distinct patterns of differential methylation and use ENCODE data to show that tumor subgroup-defining DMRs display differential chromatin state, and regulatory factor binding preferences. Finally, we characterize an epigenetic switch involving the HOXA-genes with associations to tumor differentiation states and patient prognosis.
  
  
  CONCLUSIONS
  Genome-wide DMR methylation patterns are reflected in the gene expression subtypes of UC. UC DMRs display three distinct methylation patterns, each associated with intrinsic features of the genome and differential regulatory factor binding preferences. Epigenetic inactivation of HOX-genes correlates with tumor differentiation states and may present an actionable epigenetic alteration in UC.
authors: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors: Mattias
authors: M
authors: Aine
authors: Division of Urologic Research, Department of Clinical Sciences Malmö, Lund University, Malmö, Sweden.
authors: Gottfrid
authors: G
authors: Sjödahl
authors: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors: Pontus
authors: P
authors: Eriksson
authors: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors: Srinivas
authors: S
authors: Veerla
authors: Division of Translational Cancer Research, Department of Laboratory Medicine Lund, Lund University, Lund, Sweden.
authors: David
authors: D
authors: Lindgren
authors: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors: Markus
authors: M
authors: Ringnér
authors: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.
authors: Mattias
authors: M
authors: Höglund