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PLoS Comput Biol. 2015 May 21;11(5):e1004269. doi: 10.1371/journal.pcbi.1004269. eCollection 2015 May.

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

Author information

1
Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America.
2
Department of Genetics, Geisel School of Medicine at Dartmouth, Hanover, New Hampshire, United States of America; Institute for Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth, Lebanon, New Hampshire, United States of America; Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth, Lebanon, 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.

PMID:
25996148
PMCID:
PMC4440643
DOI:
10.1371/journal.pcbi.1004269
[Indexed for MEDLINE]
Free PMC Article

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