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Androgen receptor profiling predicts prostate cancer outcome.

Stelloo S, Nevedomskaya E, van der Poel HG, de Jong J, van Leenders GJ, Jenster G, Wessels LF, Bergman AM, Zwart W - EMBO Mol Med (2015)

Bottom Line: Biomarkers for outcome prediction are urgently needed, so that high-risk patients could be monitored more closely postoperatively.These differential androgen receptor/chromatin interactions dictated expression of a distinct gene signature with strong prognostic potential.By combining existing technologies, we propose a novel pipeline for biomarker discovery that is easily implementable in other fields of oncology.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

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Expression and occupancy of a set of transcription factors corresponding to the identified motifs at FAIRE peaksExpression levels of AR, CTCF, FOXA1, ERG, ETV1, and NKX3-1 relative to TBP in four independent primary tumors. Error bars indicate SD from triplicate analysis.FAIRE-seq snapshots of accessible chromatin regions containing a CTCF motif in four primary tumors (green) and CTCF binding as assessed through ChIP-seq in LNCaP cells (red track, GSE33213).Heatmap, illustrating ChIP–qPCR-based enrichment of CTCF binding at accessible chromatin sites depicted in (B).FAIRE-seq snapshots of accessible chromatin regions containing an ERG motif in four primary tumors (green) and ERG binding as assessed through ChIP-seq in LNCaP cells (blue track, GSM1193658).Heatmap, illustrating ChIP–qPCR-based enrichment of ERG binding at accessible chromatin sites depicted in (D).
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fig07ev: Expression and occupancy of a set of transcription factors corresponding to the identified motifs at FAIRE peaksExpression levels of AR, CTCF, FOXA1, ERG, ETV1, and NKX3-1 relative to TBP in four independent primary tumors. Error bars indicate SD from triplicate analysis.FAIRE-seq snapshots of accessible chromatin regions containing a CTCF motif in four primary tumors (green) and CTCF binding as assessed through ChIP-seq in LNCaP cells (red track, GSE33213).Heatmap, illustrating ChIP–qPCR-based enrichment of CTCF binding at accessible chromatin sites depicted in (B).FAIRE-seq snapshots of accessible chromatin regions containing an ERG motif in four primary tumors (green) and ERG binding as assessed through ChIP-seq in LNCaP cells (blue track, GSM1193658).Heatmap, illustrating ChIP–qPCR-based enrichment of ERG binding at accessible chromatin sites depicted in (D).

Mentions: Subsequently, mRNA expression and DNA binding for multiple of these transcription factors were assessed in prostate tumors and cell lines. For AR, CTCF, ERG, FOXA1, ETV1, and NKX3-1, mRNA expression was confirmed in four primary tumors (FigEV1A). Using publically available ChIP-seq data from LNCaP and VCaP cells, we could illustrate these factors occupying the FAIRE-seq regions in the tumors (Fig2G). As expected, AR binding was enriched at the enhancer-associated accessible regions, while CTCF occupied both enhancers and promoters (Taslim et al, 2012). For ERG and CTCF, we further validated binding at a subset of these regions in primary tumor specimens by ChIP–qPCR (Fig EV1B–E). Functional involvement of AR was further evidenced by ingenuity pathway analysis using the list of genes corresponding to the motifs identified in FAIRE-seq peaks of the primary tumors (Table EV1). This analysis yielded functional networks known to be involved in prostate cancer, with one network centered around AR (Fig2H, Appendix Fig S3).


Androgen receptor profiling predicts prostate cancer outcome.

Stelloo S, Nevedomskaya E, van der Poel HG, de Jong J, van Leenders GJ, Jenster G, Wessels LF, Bergman AM, Zwart W - EMBO Mol Med (2015)

Expression and occupancy of a set of transcription factors corresponding to the identified motifs at FAIRE peaksExpression levels of AR, CTCF, FOXA1, ERG, ETV1, and NKX3-1 relative to TBP in four independent primary tumors. Error bars indicate SD from triplicate analysis.FAIRE-seq snapshots of accessible chromatin regions containing a CTCF motif in four primary tumors (green) and CTCF binding as assessed through ChIP-seq in LNCaP cells (red track, GSE33213).Heatmap, illustrating ChIP–qPCR-based enrichment of CTCF binding at accessible chromatin sites depicted in (B).FAIRE-seq snapshots of accessible chromatin regions containing an ERG motif in four primary tumors (green) and ERG binding as assessed through ChIP-seq in LNCaP cells (blue track, GSM1193658).Heatmap, illustrating ChIP–qPCR-based enrichment of ERG binding at accessible chromatin sites depicted in (D).
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4644377&req=5

fig07ev: Expression and occupancy of a set of transcription factors corresponding to the identified motifs at FAIRE peaksExpression levels of AR, CTCF, FOXA1, ERG, ETV1, and NKX3-1 relative to TBP in four independent primary tumors. Error bars indicate SD from triplicate analysis.FAIRE-seq snapshots of accessible chromatin regions containing a CTCF motif in four primary tumors (green) and CTCF binding as assessed through ChIP-seq in LNCaP cells (red track, GSE33213).Heatmap, illustrating ChIP–qPCR-based enrichment of CTCF binding at accessible chromatin sites depicted in (B).FAIRE-seq snapshots of accessible chromatin regions containing an ERG motif in four primary tumors (green) and ERG binding as assessed through ChIP-seq in LNCaP cells (blue track, GSM1193658).Heatmap, illustrating ChIP–qPCR-based enrichment of ERG binding at accessible chromatin sites depicted in (D).
Mentions: Subsequently, mRNA expression and DNA binding for multiple of these transcription factors were assessed in prostate tumors and cell lines. For AR, CTCF, ERG, FOXA1, ETV1, and NKX3-1, mRNA expression was confirmed in four primary tumors (FigEV1A). Using publically available ChIP-seq data from LNCaP and VCaP cells, we could illustrate these factors occupying the FAIRE-seq regions in the tumors (Fig2G). As expected, AR binding was enriched at the enhancer-associated accessible regions, while CTCF occupied both enhancers and promoters (Taslim et al, 2012). For ERG and CTCF, we further validated binding at a subset of these regions in primary tumor specimens by ChIP–qPCR (Fig EV1B–E). Functional involvement of AR was further evidenced by ingenuity pathway analysis using the list of genes corresponding to the motifs identified in FAIRE-seq peaks of the primary tumors (Table EV1). This analysis yielded functional networks known to be involved in prostate cancer, with one network centered around AR (Fig2H, Appendix Fig S3).

Bottom Line: Biomarkers for outcome prediction are urgently needed, so that high-risk patients could be monitored more closely postoperatively.These differential androgen receptor/chromatin interactions dictated expression of a distinct gene signature with strong prognostic potential.By combining existing technologies, we propose a novel pipeline for biomarker discovery that is easily implementable in other fields of oncology.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Show MeSH
Related in: MedlinePlus