TY - JOUR
T1 - Integrative epigenetic taxonomy of primary prostate cancer
AU - Stelloo, Suzan
AU - Nevedomskaya, Ekaterina
AU - Kim, Yongsoo
AU - Schuurman, Karianne
AU - Valle-Encinas, Eider
AU - Lobo, João
AU - Krijgsman, Oscar
AU - Peeper, Daniel Simon
AU - Chang, Seiwon Laura
AU - Feng, Felix Yi Chung
AU - Wessels, Lodewyk Frederik Ary
AU - Henrique, Rui
AU - Jerónimo, Carmen
AU - Bergman, Andries Marinus
AU - Zwart, Wilbert
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85056980438&partnerID=8YFLogxK
U2 - https://doi.org/10.1038/s41467-018-07270-2
DO - https://doi.org/10.1038/s41467-018-07270-2
M3 - Article
C2 - 30464211
SN - 2041-1723
VL - 9
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 4900
ER -