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Integrative epigenomic analysis of differential DNA methylation in bladder cancer

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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE58256 | GEO | 2015/05/28

SECONDARY ACCESSION(S): PRJNA251829

REPOSITORIES: GEO

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Project description:DNA methylation appears to play an essential mechanistic role in the pathogenesis of ALL, thereby potentiate its use as a biomarker for diagnosis and prognosis (Milani, Lundmark et al. 2010; Geng, Brennan et al. 2012; Sandoval, Heyn et al. 2013), and even a potential target of novel therapeutic approaches in ALL. In present study, we collected blood specimens for 4 pairs of monozygotic twins (MZ) and 1 pair of dizygotic twin (DZ) that are discordant for ALL. We sought to comprehensively assess the magnitude of genetic and epigenetic differences between ALL-affected and unaffected twins. we conducted whole genome and whole methylome sequencing on these five pairs of ALL-discordant twins. We also examined both the MZ and DZ twins using whole-genome bisulfite sequencing (WGBS). At first, the methylation differences across the genome were addressed globally by Circos software. And then tried to characterize the co-twin methylation divergence in specific genomic regions between ALL-discordant twin pairs. These patterns of dynamic co-twin methylation changes in these discordant ALL samples were generally consistent among MZ and DZ twins, indicating similarities of methylation abnormalities. As a result, 780, 566, 309, 293 and 2110 DMRs were identified, with a similar distribution pattern across different genomic elements among the five twin pairs.Then we annotate whether these DMRs were located in regulatory elements and identification of genes with recurring methylation alterations in a cohort of ALL patients. We collected blood specimens from 4 pairs of MZ twins and 1 pair of DZ twin that are discordant for ALL. At first, the methylation differences across the genome were addressed globally by Circos software. And then tried to characterize the co-twin methylation divergence in specific genomic regions and differentially methylated gene regions (DMRs) were identified between ALL-discordant twin pairs. Then we annotate whether these DMRs were located in regulatory elements and identification of genes with recurring methylation alterations in a cohort of ALL patients.

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Integrative epigenomic analysis of differential DNA methylation in bladder cancer

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