title: Androgen receptor profiling predicts prostate cancer outcome.
abstract: Prostate cancer is the second most prevalent malignancy in men. Biomarkers for outcome prediction are urgently needed, so that high-risk patients could be monitored more closely postoperatively. To identify prognostic markers and to determine causal players in prostate cancer progression, we assessed changes in chromatin state during tumor development and progression. Based on this, we assessed genomewide androgen receptor/chromatin binding and identified a distinct androgen receptor/chromatin binding profile between primary prostate cancers and tumors with an acquired resistance to therapy. These differential androgen receptor/chromatin interactions dictated expression of a distinct gene signature with strong prognostic potential. Further refinement of the signature provided us with a concise list of nine genes that hallmark prostate cancer outcome in multiple independent validation series. In this report, we identified a novel gene expression signature for prostate cancer outcome through generation of multilevel genomic data on chromatin accessibility and transcriptional regulation and integration with publically available transcriptomic and clinical datastreams. By combining existing technologies, we propose a novel pipeline for biomarker discovery that is easily implementable in other fields of oncology.
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Suzan
authors.initials: S
authors.lastname: Stelloo
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Nevedomskaya
authors.affiliation: Division of Urology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Henk G
authors.initials: HG
authors.lastname: van der Poel
authors.affiliation: Division of Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Jeroen
authors.initials: J
authors.lastname: de Jong
authors.affiliation: Department of Pathology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Geert J L H
authors.initials: GJ
authors.lastname: van Leenders
authors.affiliation: Department of Urology, Josephine Nefkens Institute, Erasmus Medical Center, Rotterdam, The Netherlands.
authors.forename: Guido
authors.initials: G
authors.lastname: Jenster
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
authors.affiliation: Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, The Netherlands a.bergman@nki.nl w.zwart@nki.nl.
authors.forename: Andries M
authors.initials: AM
authors.lastname: Bergman
authors.affiliation: Division of Molecular Pathology, The Netherlands Cancer Institute, Amsterdam, The Netherlands a.bergman@nki.nl w.zwart@nki.nl.
authors.forename: Wilbert
authors.initials: W
authors.lastname: Zwart
mesh_terms: D014408:Biomarkers, Tumor / Q000032:analysis*; D002843:Chromatin / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D057089:Pathology, Molecular / Q000379:methods*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000473:pathology*; D011944:Receptors, Androgen / Q000378:metabolism*
chemical_list: D014408:Biomarkers, Tumor; D002843:Chromatin; D011944:Receptors, Androgen
keywords: ChIP‐seq; FAIRE‐seq; androgen receptor profiling; companion diagnostics for prostate cancer; treatment prediction