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Nat Commun. 2018 Nov 21;9(1):4900. doi: 10.1038/s41467-018-07270-2.

Integrative epigenetic taxonomy of primary prostate cancer.

Author information

1
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
2
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
3
Cancer Biology and Epigenetics Group, Research Center of the Portuguese Oncology Institute-Porto, Porto, 4200-072, Portugal.
4
Department of Pathology, Portuguese Oncology Institute of Porto, Porto, 4200-072, Portugal.
5
Department of Pathology and Molecular Immunology, Institute of Biomedical Sciences Abel Salazar (ICBAS), University of Porto, Porto, 4050-313, Portugal.
6
Division of Molecular Oncology & Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
7
Department of Radiation Oncology, Helen Diller Family Comprehensive Cancer Center, University of California San Francisco (UCSF), San Francisco, CA, 94115, USA.
8
Faculty of EEMCS, Delft University of Technology, Delft, 2628 CD, The Netherlands.
9
Division of Medical Oncology, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. a.bergman@nki.nl.
10
Division of Oncogenomics, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. a.bergman@nki.nl.
11
Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands. w.zwart@nki.nl.
12
Laboratory of Chemical Biology and Institute for Complex Molecular Systems, Department of Biomedical Engineering, Eindhoven University of Technology, PO Box 513, Eindhoven, 5600 MB, The Netherlands. w.zwart@nki.nl.

Abstract

The Androgen Receptor (AR) is the key-driving transcription factor in prostate cancer, tightly controlled by epigenetic regulation. To date, most epigenetic profiling has been performed in cell lines or limited tissue samples. Here, to comprehensively study the epigenetic landscape, we perform RNA-seq with ChIP-seq for AR and histone modification marks (H3K27ac, H3K4me3, H3K27me3) in 100 primary prostate carcinomas. Integrative molecular subtyping of the five data streams revealed three major subtypes of which two were clearly TMPRSS2-ERG dictated. Importantly, we identify a third subtype with low chromatin binding and activity of AR, but with high activity of FGF and WNT signaling. While positive for neuroendocrine-hallmark genes, these tumors were copy number-neutral with low mutational burden, significantly depleted for genes characteristic of poor-outcome associated luminal B-subtype. We present a unique resource on transcriptional and epigenetic control in prostate cancer, revealing tight control of gene regulation differentially dictated by AR over three subtypes.

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