Integrative epigenetic taxonomy of primary prostate cancer
Suzan Stelloo (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
E Nevedomskaya (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Yongsoo Kim (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Karianne Schuurman (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Eider Valle-Encinas (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
João Lobo (Universidade do Porto)
Oscar Krijgsman (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Daniel Simon Peeper (Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
Seiwon Laura Chang (University of California)
Lodewyk F. Wessels (TU Delft - Pattern Recognition and Bioinformatics, Nederlands Kanker Instituut - Antoni van Leeuwenhoek ziekenhuis)
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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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