Romanel Alessandro, Garritano Sonia, Stringa Blerta, Blattner Mirjam, Dalfovo Davide, Chakravarty Dimple, Soong David, Cotter Kellie A, Petris Gianluca, Dhingra Priyanka, Gasperini Paola, Cereseto Anna, Elemento Olivier, Sboner Andrea, Khurana Ekta, Inga Alberto, Rubin Mark A, Demichelis Francesca
Centre for Integrative Biology, University of Trento, Via Sommarive 9, 38123, Trento, Italy.
Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, 413 East 69th Street, New York, NY, 10021, USA.
Nat Commun. 2017 Jun 29;8(1):48. doi: 10.1038/s41467-017-00046-0.
Prostate cancer is a highly heritable molecularly and clinically heterogeneous disease. To discover germline events involved in prostate cancer predisposition, we develop a computational approach to nominate heritable facilitators of somatic genomic events in the context of the androgen receptor signaling. Here, we use a ranking score and benign prostate transcriptomes to identify a non-coding polymorphic regulatory element at 7p14.3 that associates with DNA repair and hormone-regulated transcript levels and with an early recurrent prostate cancer-specific somatic mutation in the Speckle-Type POZ protein (SPOP) gene. The locus shows allele-specific activity that is concomitantly modulated by androgen receptor and by CCAAT/enhancer-binding protein (C/EBP) beta (CEBPB). Deletion of this locus via CRISPR-Cas9 leads to deregulation of the genes predicted to interact with the 7p14.3 locus by Hi-C chromosome conformation capture data. This study suggests that a polymorphism at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone-dependent DNA damage response.Prostate cancer is a heterogeneous disease, and many cases show somatic mutations of SPOP. Here, the authors show that a non-coding polymorphic regulatory element at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone dependent DNA damage response.
前列腺癌是一种具有高度遗传性的分子和临床异质性疾病。为了发现参与前列腺癌易感性的种系事件，我们开发了一种计算方法，在雄激素受体信号传导的背景下，提名体细胞基因组事件的可遗传促进因子。在这里，我们使用一个排名分数和良性前列腺转录组来鉴定7p14.3处的一个非编码多态性调控元件，该元件与DNA修复和激素调节的转录水平相关，并与斑点型POZ蛋白（SPOP）基因中的一种早期复发性前列腺癌特异性体细胞突变相关。该基因座显示出等位基因特异性活性，其同时受到雄激素受体和CCAAT/增强子结合蛋白（C/EBP）β（CEBPB）的调节。通过CRISPR-Cas9删除该基因座会导致通过Hi-C染色体构象捕获数据预测与7p14.3基因座相互作用的基因失调。这项研究表明，7p14.3处的多态性可能通过激素依赖性DNA损伤反应使个体易患SPOP突变型前列腺癌亚类。前列腺癌是一种异质性疾病，许多病例显示出SPOP的体细胞突变。在这里，作者表明，7p14.3处的一个非编码多态性调控元件可能通过激素依赖性DNA损伤反应使个体易患SPOP突变型前列腺癌亚类。
