Division of Oncogenomics, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, 1066 CX, The Netherlands.
Nat Commun. 2018 Nov 21;9(1):4900. doi: 10.1038/s41467-018-07270-2.
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.
雄激素受体 (AR) 是前列腺癌的关键转录因子，受表观遗传调控的严密控制。迄今为止，大多数表观遗传分析都是在细胞系或有限的组织样本中进行的。在这里，为了全面研究表观遗传景观，我们对 100 例原发性前列腺癌进行了 AR 和组蛋白修饰标记 (H3K27ac、H3K4me3、H3K27me3) 的 RNA-seq 和 ChIP-seq。五个数据流的综合分子亚分型揭示了三个主要亚型，其中两个明显是由 TMPRSS2-ERG 决定的。重要的是，我们确定了第三个亚型，其染色质结合和 AR 活性较低，但 FGF 和 WNT 信号活性较高。这些肿瘤虽然具有神经内分泌标志物基因的阳性，但拷贝数为中性，突变负担低，与 luminal B 亚型不良预后相关的基因明显缺失。我们提供了前列腺癌转录和表观遗传控制的独特资源，揭示了 AR 通过三个亚型对基因调控的严密控制。
