Abstract
BackgroundUrothelial 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.MethodsWe 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.ResultsWe 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.ConclusionsGenome-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.Electronic supplementary materialThe online version of this article (doi:10.1186/s13073-015-0144-4) contains supplementary material, which is available to authorized users.
Highlights
Urothelial carcinoma of the bladder (UC) is a common malignancy
To address this gap and investigate the interrelations between gene expression and DNA methylation profiles, we identified differentially methylated regions (DMRs) from methylated DNA immunoprecipitation on chip (MeDIP-chip) data generated for 98 UC tumors
To define subgroups of UC based on their DMR methylation profiles, we used the 25% most varying DMRs (N = 1,363) and a bootstrap hierarchical clustering approach for tumor sample clustering [21]
Summary
Urothelial carcinoma of the bladder (UC) is a common malignancy. extensive transcriptome analysis has provided insights into the gene expression patterns of this tumor type, the mechanistic underpinnings of differential methylation remain poorly understood. The interrelations between the gene expression phenotype, the genome, as well as the DNA methylation landscape has been extensively investigated across different malignancies [7,8]. Few studies have investigated the epigenomic landscape of UC These have highlighted aberrant expression of epigenetic writers, silencing of developmental genes, as well as topological effects on the level of histone modifications as prominent features of aggressive UC [9,10,11]. This study used mRNA expression data to stratify the tumors, it did not report on the interrelations between the gene expression phenotype and the underlying DNA methylation subtypes of UC, but instead focused on the mutation and genomic landscapes
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
