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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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Distinct AR binding profiles in primary and treatment-resistant tumorsOverview of experimental design. DNA and proteins were cross-linked using formaldehyde, followed by shearing of the chromatin. Immunoprecipitation for AR was performed after which isolated DNA fragments were sequenced.Snapshots of AR binding events differentially enriched in either primary (green) or resistant (red) tumors. Reads are normalized to millions of sequenced reads per sample. Genomic coordinates are shown.Heatmap illustrating AR ChIP-qPCR validation in independent tumors. Intensity of the color corresponds to ChIP–qPCR enrichment (see scale bar). Binding sites identified as enriched in either primary or treatment-resistant tumors were tested. Average enrichment in primary tumors was divided over average resistant enrichment values to determine the ratio, as is visualized in a barplot (bottom panel).Differential binding analysis of AR chromatin binding regions, selectively enriched in primary tumors (green) or treatment-resistant (red) tumors.Average read counts for AR binding events, selectively enriched between primary (green) or resistant (red) tumors. Data are centered at AR peaks, depicting a 2.5-kb window around the peak.Genomic distributions of AR binding sites shared between tumors or enriched in primary and resistant tumor tissue.Distribution of AR binding sites enriched in primary (green) and resistant (red) tumors, by chromosome (%). P-values (one-sided binomial test) for significant enrichment relative to the entire genome (gray): (a) P = 0.001, (b) P = 0.002, (c) P = 0.003, (d) P = 0.005, (e) P = 9e−13, and (f) P = 2.5e−13.Motif enrichment analysis for AR binding sites shared between tumors or enriched in primary and resistant tumor tissue. Top motifs are shown.
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fig03: Distinct AR binding profiles in primary and treatment-resistant tumorsOverview of experimental design. DNA and proteins were cross-linked using formaldehyde, followed by shearing of the chromatin. Immunoprecipitation for AR was performed after which isolated DNA fragments were sequenced.Snapshots of AR binding events differentially enriched in either primary (green) or resistant (red) tumors. Reads are normalized to millions of sequenced reads per sample. Genomic coordinates are shown.Heatmap illustrating AR ChIP-qPCR validation in independent tumors. Intensity of the color corresponds to ChIP–qPCR enrichment (see scale bar). Binding sites identified as enriched in either primary or treatment-resistant tumors were tested. Average enrichment in primary tumors was divided over average resistant enrichment values to determine the ratio, as is visualized in a barplot (bottom panel).Differential binding analysis of AR chromatin binding regions, selectively enriched in primary tumors (green) or treatment-resistant (red) tumors.Average read counts for AR binding events, selectively enriched between primary (green) or resistant (red) tumors. Data are centered at AR peaks, depicting a 2.5-kb window around the peak.Genomic distributions of AR binding sites shared between tumors or enriched in primary and resistant tumor tissue.Distribution of AR binding sites enriched in primary (green) and resistant (red) tumors, by chromosome (%). P-values (one-sided binomial test) for significant enrichment relative to the entire genome (gray): (a) P = 0.001, (b) P = 0.002, (c) P = 0.003, (d) P = 0.005, (e) P = 9e−13, and (f) P = 2.5e−13.Motif enrichment analysis for AR binding sites shared between tumors or enriched in primary and resistant tumor tissue. Top motifs are shown.

Mentions: Since AR and its interactors were enriched at FAIRE-seq regions (Fig2G), we next performed AR ChIP-seq on five primary and three treatment-resistant tumor specimens (Fig3A). The number of reads and AR binding events is shown in Appendix Table S4. The total number of identified AR binding events greatly varied between the tumor samples (Appendix Table S4), which is consistent with previous nuclear receptor ChIP-seq in prostate and breast tumor samples (Ross-Innes et al, 2012; Jansen et al, 2013; Sharma et al, 2013). Specifically, our AR binding sites varied from 238 up to 17,511 per tumor sample, which is in the same order of magnitude as in Sharma et al, with 300–8,500 per tumor sample (Sharma et al, 2013).


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)

Distinct AR binding profiles in primary and treatment-resistant tumorsOverview of experimental design. DNA and proteins were cross-linked using formaldehyde, followed by shearing of the chromatin. Immunoprecipitation for AR was performed after which isolated DNA fragments were sequenced.Snapshots of AR binding events differentially enriched in either primary (green) or resistant (red) tumors. Reads are normalized to millions of sequenced reads per sample. Genomic coordinates are shown.Heatmap illustrating AR ChIP-qPCR validation in independent tumors. Intensity of the color corresponds to ChIP–qPCR enrichment (see scale bar). Binding sites identified as enriched in either primary or treatment-resistant tumors were tested. Average enrichment in primary tumors was divided over average resistant enrichment values to determine the ratio, as is visualized in a barplot (bottom panel).Differential binding analysis of AR chromatin binding regions, selectively enriched in primary tumors (green) or treatment-resistant (red) tumors.Average read counts for AR binding events, selectively enriched between primary (green) or resistant (red) tumors. Data are centered at AR peaks, depicting a 2.5-kb window around the peak.Genomic distributions of AR binding sites shared between tumors or enriched in primary and resistant tumor tissue.Distribution of AR binding sites enriched in primary (green) and resistant (red) tumors, by chromosome (%). P-values (one-sided binomial test) for significant enrichment relative to the entire genome (gray): (a) P = 0.001, (b) P = 0.002, (c) P = 0.003, (d) P = 0.005, (e) P = 9e−13, and (f) P = 2.5e−13.Motif enrichment analysis for AR binding sites shared between tumors or enriched in primary and resistant tumor tissue. Top motifs are shown.
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fig03: Distinct AR binding profiles in primary and treatment-resistant tumorsOverview of experimental design. DNA and proteins were cross-linked using formaldehyde, followed by shearing of the chromatin. Immunoprecipitation for AR was performed after which isolated DNA fragments were sequenced.Snapshots of AR binding events differentially enriched in either primary (green) or resistant (red) tumors. Reads are normalized to millions of sequenced reads per sample. Genomic coordinates are shown.Heatmap illustrating AR ChIP-qPCR validation in independent tumors. Intensity of the color corresponds to ChIP–qPCR enrichment (see scale bar). Binding sites identified as enriched in either primary or treatment-resistant tumors were tested. Average enrichment in primary tumors was divided over average resistant enrichment values to determine the ratio, as is visualized in a barplot (bottom panel).Differential binding analysis of AR chromatin binding regions, selectively enriched in primary tumors (green) or treatment-resistant (red) tumors.Average read counts for AR binding events, selectively enriched between primary (green) or resistant (red) tumors. Data are centered at AR peaks, depicting a 2.5-kb window around the peak.Genomic distributions of AR binding sites shared between tumors or enriched in primary and resistant tumor tissue.Distribution of AR binding sites enriched in primary (green) and resistant (red) tumors, by chromosome (%). P-values (one-sided binomial test) for significant enrichment relative to the entire genome (gray): (a) P = 0.001, (b) P = 0.002, (c) P = 0.003, (d) P = 0.005, (e) P = 9e−13, and (f) P = 2.5e−13.Motif enrichment analysis for AR binding sites shared between tumors or enriched in primary and resistant tumor tissue. Top motifs are shown.
Mentions: Since AR and its interactors were enriched at FAIRE-seq regions (Fig2G), we next performed AR ChIP-seq on five primary and three treatment-resistant tumor specimens (Fig3A). The number of reads and AR binding events is shown in Appendix Table S4. The total number of identified AR binding events greatly varied between the tumor samples (Appendix Table S4), which is consistent with previous nuclear receptor ChIP-seq in prostate and breast tumor samples (Ross-Innes et al, 2012; Jansen et al, 2013; Sharma et al, 2013). Specifically, our AR binding sites varied from 238 up to 17,511 per tumor sample, which is in the same order of magnitude as in Sharma et al, with 300–8,500 per tumor sample (Sharma et al, 2013).

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