GSE65478
Androgen Receptor profiling in tumor specimens yields hallmarks of prostate cancer outcome
Prostate cancer is the most prevalent malignancy in men. Biomarkers for outcome prediction are urgently needed, since high-risk patients may benefit from additional therapy at early stages of the disease, greatly increasing the chance for cure. To identify prognostic markers and to determine causal players in prostate cancer progression, we assessed changes in chromatin state during tumor development and progression.  In addition, we 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 in another cohort of prostate cancer patients. 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 integration of multilevel genomic data on chromatin accessibility and transcriptional regulation with publicly available transcriptomic and clinical datastreams. With this, we present a highly innovative pipeline for biomarker discovery that is easily implementable in other fields of oncology.  Overall design: Accessible chromatin was mapped genome-wide by FAIRE-Seq (Formaldehyde-Assisted Isolation of Regulatory Elements) in 4 primary, 3 hormonal therapy-resistant and 3 metastatic prostate cancers, as well as in 4 normal prostate specimens. Androgen receptor (AR) binding to DNA was profiled by ChIP-seq (Chromatin Immunoprecipitation) genome-wide in 4 primary and 3 therapy-resistant prostate tumors.