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Regulators associated with clinical outcomes revealed by DNA methylation data in breast cancer.

Ung MH, Varn FS, Lou S, Cheng C - PLoS Comput. Biol. (2015)

Bottom Line: This dysfunctional process typically involves additional regulatory modulators including DNA methylation.Our analysis identified TFs known to be associated with clinical outcomes of p53 and ER (estrogen receptor) subtypes of breast cancer, while also predicting new TFs that may also be involved.Overall, this study provides a comprehensive analysis that links DNA methylation to TF binding to patient prognosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

ABSTRACT
The regulatory architecture of breast cancer is extraordinarily complex and gene misregulation can occur at many levels, with transcriptional malfunction being a major cause. This dysfunctional process typically involves additional regulatory modulators including DNA methylation. Thus, the interplay between transcription factor (TF) binding and DNA methylation are two components of a cancer regulatory interactome presumed to display correlated signals. As proof of concept, we performed a systematic motif-based in silico analysis to infer all potential TFs that are involved in breast cancer prognosis through an association with DNA methylation changes. Using breast cancer DNA methylation and clinical data derived from The Cancer Genome Atlas (TCGA), we carried out a systematic inference of TFs whose misregulation underlie different clinical subtypes of breast cancer. Our analysis identified TFs known to be associated with clinical outcomes of p53 and ER (estrogen receptor) subtypes of breast cancer, while also predicting new TFs that may also be involved. Furthermore, our results suggest that misregulation in breast cancer can be caused by the binding of alternative factors to the binding sites of TFs whose activity has been ablated. Overall, this study provides a comprehensive analysis that links DNA methylation to TF binding to patient prognosis.

No MeSH data available.


Related in: MedlinePlus

TF binding motifs enriched in histological and intrinsic subtypes of breast cancer.A) Hierarchical clustering of -log10(P-values) of TF motifs enriched in histological breast cancer subtypes. Only TF motifs enriched with P<0.05 were included in the clustering procedure. B) Enrichment values of TR-NF1_Q6 in triple-negative breast cancer. C) Hierarchical clustering of -log10(P-values) of TF binding motifs in intrinsic breast cancer subtypes. D) Enrichment values of JA-ELK1 in basal breast cancer. A, C) Enrichment of motifs is shown in blue and depletion is shown in yellow.
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pcbi.1004269.g005: TF binding motifs enriched in histological and intrinsic subtypes of breast cancer.A) Hierarchical clustering of -log10(P-values) of TF motifs enriched in histological breast cancer subtypes. Only TF motifs enriched with P<0.05 were included in the clustering procedure. B) Enrichment values of TR-NF1_Q6 in triple-negative breast cancer. C) Hierarchical clustering of -log10(P-values) of TF binding motifs in intrinsic breast cancer subtypes. D) Enrichment values of JA-ELK1 in basal breast cancer. A, C) Enrichment of motifs is shown in blue and depletion is shown in yellow.

Mentions: Second, we clustered the p-values (P<0.05) of significantly enriched or depleted TF binding motifs in survival-associated CpGs and observed that PR+ and ER+, which clustered together, exhibited enrichment patterns much different from that of the other subtypes (Fig 5A). More specifically, these subtypes are enriched in TF binding sites that are depleted in the other subtypes and vice versa. This suggests that the TFs associated with survival in PR+ and ER+ samples may not be significant protein factors in the other subtypes. In addition, it is clear that significantly enriched/depleted TF binding motifs vary from subtype to subtype implying that each subtype exhibits distinct TF-DNA methylation interactions. This shows that unique enrichment signatures can differentiate between breast cancer subtypes by revealing transcriptional regulators most likely to exhibit altered activity.


Regulators associated with clinical outcomes revealed by DNA methylation data in breast cancer.

Ung MH, Varn FS, Lou S, Cheng C - PLoS Comput. Biol. (2015)

TF binding motifs enriched in histological and intrinsic subtypes of breast cancer.A) Hierarchical clustering of -log10(P-values) of TF motifs enriched in histological breast cancer subtypes. Only TF motifs enriched with P<0.05 were included in the clustering procedure. B) Enrichment values of TR-NF1_Q6 in triple-negative breast cancer. C) Hierarchical clustering of -log10(P-values) of TF binding motifs in intrinsic breast cancer subtypes. D) Enrichment values of JA-ELK1 in basal breast cancer. A, C) Enrichment of motifs is shown in blue and depletion is shown in yellow.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4440643&req=5

pcbi.1004269.g005: TF binding motifs enriched in histological and intrinsic subtypes of breast cancer.A) Hierarchical clustering of -log10(P-values) of TF motifs enriched in histological breast cancer subtypes. Only TF motifs enriched with P<0.05 were included in the clustering procedure. B) Enrichment values of TR-NF1_Q6 in triple-negative breast cancer. C) Hierarchical clustering of -log10(P-values) of TF binding motifs in intrinsic breast cancer subtypes. D) Enrichment values of JA-ELK1 in basal breast cancer. A, C) Enrichment of motifs is shown in blue and depletion is shown in yellow.
Mentions: Second, we clustered the p-values (P<0.05) of significantly enriched or depleted TF binding motifs in survival-associated CpGs and observed that PR+ and ER+, which clustered together, exhibited enrichment patterns much different from that of the other subtypes (Fig 5A). More specifically, these subtypes are enriched in TF binding sites that are depleted in the other subtypes and vice versa. This suggests that the TFs associated with survival in PR+ and ER+ samples may not be significant protein factors in the other subtypes. In addition, it is clear that significantly enriched/depleted TF binding motifs vary from subtype to subtype implying that each subtype exhibits distinct TF-DNA methylation interactions. This shows that unique enrichment signatures can differentiate between breast cancer subtypes by revealing transcriptional regulators most likely to exhibit altered activity.

Bottom Line: This dysfunctional process typically involves additional regulatory modulators including DNA methylation.Our analysis identified TFs known to be associated with clinical outcomes of p53 and ER (estrogen receptor) subtypes of breast cancer, while also predicting new TFs that may also be involved.Overall, this study provides a comprehensive analysis that links DNA methylation to TF binding to patient prognosis.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.

ABSTRACT
The regulatory architecture of breast cancer is extraordinarily complex and gene misregulation can occur at many levels, with transcriptional malfunction being a major cause. This dysfunctional process typically involves additional regulatory modulators including DNA methylation. Thus, the interplay between transcription factor (TF) binding and DNA methylation are two components of a cancer regulatory interactome presumed to display correlated signals. As proof of concept, we performed a systematic motif-based in silico analysis to infer all potential TFs that are involved in breast cancer prognosis through an association with DNA methylation changes. Using breast cancer DNA methylation and clinical data derived from The Cancer Genome Atlas (TCGA), we carried out a systematic inference of TFs whose misregulation underlie different clinical subtypes of breast cancer. Our analysis identified TFs known to be associated with clinical outcomes of p53 and ER (estrogen receptor) subtypes of breast cancer, while also predicting new TFs that may also be involved. Furthermore, our results suggest that misregulation in breast cancer can be caused by the binding of alternative factors to the binding sites of TFs whose activity has been ablated. Overall, this study provides a comprehensive analysis that links DNA methylation to TF binding to patient prognosis.

No MeSH data available.


Related in: MedlinePlus