Androgen receptor profiling predicts prostate cancer outcome.
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.
Affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.Show MeSH
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Mentions: We assessed chromatin accessibility in multiple prostate tissue specimens as well as the changes thereof in prostate cancer development and progression. Four normal prostate tissue samples, four primary tumors, and three ADT-resistant prostate tumors were assessed, as well as three prostate cancer metastases (Fig2A). FAIRE-seq was applied to identify accessible chromatin regions with gene-regulatory functions on a genomewide scale (Giresi & Lieb, 2009). FAIRE is based on phenol–chloroform mediated sample separation, in which accessible chromatin fragments can be separated from the condensed state, effectively enriching for regulatory genomic regions (schematically visualized in Fig2A). Metastases and prostate adenocarcinomas contained more than 70% tumor cells with a Gleason score ranging from 7 (3 + 4) to 10 (5 + 5), while all normal prostate tissues were derived from a healthy region from prostatectomy specimens. Tumor and normal tissues were validated by our pathologists. Clinicopathological parameters are shown in Appendix Table S1. The number of FAIRE peaks identified was highly variable between the tissues, ranging from 50 peaks up to over 13,000 peaks (Appendix Table S2). Figure2B shows four randomly selected representative coverage profiles of accessible chromatin at promoter regions. Over 50% of accessible chromatin sites in healthy and tumor specimens were found at promoter regions (Fig2C), and average signal for each specimen showed clear enrichment of reads at transcription start sites (Appendix Fig S1). Tumor samples showed more enriched chromatin accessibility at both intron and distal intergenic regions, as opposed to normal prostate tissue where FAIRE signal was mainly found at promoters (Fig2C).
Affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.