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Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma.

Aine M, Sjödahl G, Eriksson P, Veerla S, Lindgren D, Ringnér M, Höglund M - Genome Med (2015)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus

Methylations patterns in the HOXA locus. (A) Genomic map of the HOXA region with UC DMRs indicated (yellow). (B) UC samples were clustered (k-means, k = 3) based on their methylation profiles across the HOXA-locus into three groups of samples (posterior-only, anterior-only, and pan-HOXA). For each sample group, the average methylation for each DMR is shown across the HOXA locus. Vertical bars denote standard deviations. (C) DMR methylation and gene expression levels across the HOXA and HOXB loci. Within the heatmaps for HOXA, the horizontal lines separate the anterior region from the posterior region (between the HOXA7 and HOXA9 promoters). The DMRs and genes are in the same order as in panel A and DNA methylation is indicated in blue (low) to red (high) and gene expression in green (low) to red (high). (D) Survival analysis of UC samples stratified into the three HOXA methylation groups. Disease-specific survival (DSS) was used as endpoint. (E, F) Coordinated changes in DMR methylation and gene expression (GEX) were visualized using starburst plots for ‘pan-HOXA’ vs. ‘posterior-only’ (E) and ‘anterior-only’ vs. ‘posterior-only’ (F). Dotted lines indicate the significance threshold FDR <0.01 (t-test).
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Fig6: Methylations patterns in the HOXA locus. (A) Genomic map of the HOXA region with UC DMRs indicated (yellow). (B) UC samples were clustered (k-means, k = 3) based on their methylation profiles across the HOXA-locus into three groups of samples (posterior-only, anterior-only, and pan-HOXA). For each sample group, the average methylation for each DMR is shown across the HOXA locus. Vertical bars denote standard deviations. (C) DMR methylation and gene expression levels across the HOXA and HOXB loci. Within the heatmaps for HOXA, the horizontal lines separate the anterior region from the posterior region (between the HOXA7 and HOXA9 promoters). The DMRs and genes are in the same order as in panel A and DNA methylation is indicated in blue (low) to red (high) and gene expression in green (low) to red (high). (D) Survival analysis of UC samples stratified into the three HOXA methylation groups. Disease-specific survival (DSS) was used as endpoint. (E, F) Coordinated changes in DMR methylation and gene expression (GEX) were visualized using starburst plots for ‘pan-HOXA’ vs. ‘posterior-only’ (E) and ‘anterior-only’ vs. ‘posterior-only’ (F). Dotted lines indicate the significance threshold FDR <0.01 (t-test).

Mentions: We identified 12 DMRs in the HOXA- and 15 DMRs in the HOXB locus (Figure 6A), of which a majority exhibited significant negative correlations to mRNA expression. The same effect was observed for a minority of HOXC and HOXD cluster genes. We noticed that the entire HOXB locus behaved as one block with respect to DNA methylation and gene expression. Conversely, there was a distinct anti-correlation between the 5’ (posterior) and 3’ (anterior) HOXA genes across samples on both the methylation and gene expression levels.Figure 6


Integrative epigenomic analysis of differential DNA methylation in urothelial carcinoma.

Aine M, Sjödahl G, Eriksson P, Veerla S, Lindgren D, Ringnér M, Höglund M - Genome Med (2015)

Methylations patterns in the HOXA locus. (A) Genomic map of the HOXA region with UC DMRs indicated (yellow). (B) UC samples were clustered (k-means, k = 3) based on their methylation profiles across the HOXA-locus into three groups of samples (posterior-only, anterior-only, and pan-HOXA). For each sample group, the average methylation for each DMR is shown across the HOXA locus. Vertical bars denote standard deviations. (C) DMR methylation and gene expression levels across the HOXA and HOXB loci. Within the heatmaps for HOXA, the horizontal lines separate the anterior region from the posterior region (between the HOXA7 and HOXA9 promoters). The DMRs and genes are in the same order as in panel A and DNA methylation is indicated in blue (low) to red (high) and gene expression in green (low) to red (high). (D) Survival analysis of UC samples stratified into the three HOXA methylation groups. Disease-specific survival (DSS) was used as endpoint. (E, F) Coordinated changes in DMR methylation and gene expression (GEX) were visualized using starburst plots for ‘pan-HOXA’ vs. ‘posterior-only’ (E) and ‘anterior-only’ vs. ‘posterior-only’ (F). Dotted lines indicate the significance threshold FDR <0.01 (t-test).
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Related In: Results  -  Collection

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Fig6: Methylations patterns in the HOXA locus. (A) Genomic map of the HOXA region with UC DMRs indicated (yellow). (B) UC samples were clustered (k-means, k = 3) based on their methylation profiles across the HOXA-locus into three groups of samples (posterior-only, anterior-only, and pan-HOXA). For each sample group, the average methylation for each DMR is shown across the HOXA locus. Vertical bars denote standard deviations. (C) DMR methylation and gene expression levels across the HOXA and HOXB loci. Within the heatmaps for HOXA, the horizontal lines separate the anterior region from the posterior region (between the HOXA7 and HOXA9 promoters). The DMRs and genes are in the same order as in panel A and DNA methylation is indicated in blue (low) to red (high) and gene expression in green (low) to red (high). (D) Survival analysis of UC samples stratified into the three HOXA methylation groups. Disease-specific survival (DSS) was used as endpoint. (E, F) Coordinated changes in DMR methylation and gene expression (GEX) were visualized using starburst plots for ‘pan-HOXA’ vs. ‘posterior-only’ (E) and ‘anterior-only’ vs. ‘posterior-only’ (F). Dotted lines indicate the significance threshold FDR <0.01 (t-test).
Mentions: We identified 12 DMRs in the HOXA- and 15 DMRs in the HOXB locus (Figure 6A), of which a majority exhibited significant negative correlations to mRNA expression. The same effect was observed for a minority of HOXC and HOXD cluster genes. We noticed that the entire HOXB locus behaved as one block with respect to DNA methylation and gene expression. Conversely, there was a distinct anti-correlation between the 5’ (posterior) and 3’ (anterior) HOXA genes across samples on both the methylation and gene expression levels.Figure 6

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Division of Oncology and Pathology, Department of Clinical Sciences Lund, Lund University, Lund, Sweden.

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.

No MeSH data available.


Related in: MedlinePlus