综合分析强调了转移性前列腺癌中三维基因组与 DNA、RNA 和表观基因组改变之间的相互作用。
Integrated analyses highlight interactions between the three-dimensional genome and DNA, RNA and epigenomic alterations in metastatic prostate cancer.
发表日期：2024 Aug
作者：
Shuang G Zhao, Matthew Bootsma, Stanley Zhou, Raunak Shrestha, Thaidy Moreno-Rodriguez, Arian Lundberg, Chu Pan, Christopher Arlidge, James R Hawley, Adam Foye, Alana S Weinstein, Martin Sjöström, Meng Zhang, Haolong Li, Lisa N Chesner, Nicholas R Rydzewski, Kyle T Helzer, Yue Shi, , Molly Lynch, Scott M Dehm, Joshua M Lang, Joshi J Alumkal, Hansen H He, Alexander W Wyatt, Rahul Aggarwal, Wilbert Zwart, Eric J Small, David A Quigley, Mathieu Lupien, Felix Y Feng
来源：
NATURE GENETICS
摘要：
基因组三维结构变异的影响已被认识到，但实体癌组织研究有限。在这里，我们对来自转移性去势抵抗性前列腺癌患者的 80 个活检样本进行了集成的深度 Hi-C 测序，以及匹配的全基因组测序、全基因组亚硫酸氢盐测序、5-羟甲基胞嘧啶 (5hmC) 测序和 RNA 测序。 A 和 B（开放和封闭）染色质区室之间的基因表达、5-甲基胞嘧啶/5hmC 甲基化以及结构变异与突变率之间存在显着差异。一部分肿瘤在 AR 基因座处表现出区域染色质接触耗尽，与染色体外环状 DNA (ecDNA) 相关，并且对 AR 信号抑制剂的反应较差。我们还确定了与甲基化结构、基因表达和预后的明显差异相关的拓扑亚型。我们的数据表明，DNA 相互作用可能导致结构变异的形成，反复出现的 TMPRSS2-ERG 融合就是例证。这种全面的整合测序工作代表了独特的临床肿瘤资源。© 2024。作者。
The impact of variations in the three-dimensional structure of the genome has been recognized, but solid cancer tissue studies are limited. Here, we performed integrated deep Hi-C sequencing with matched whole-genome sequencing, whole-genome bisulfite sequencing, 5-hydroxymethylcytosine (5hmC) sequencing and RNA sequencing across a cohort of 80 biopsy samples from patients with metastatic castration-resistant prostate cancer. Dramatic differences were present in gene expression, 5-methylcytosine/5hmC methylation and in structural variation versus mutation rate between A and B (open and closed) chromatin compartments. A subset of tumors exhibited depleted regional chromatin contacts at the AR locus, linked to extrachromosomal circular DNA (ecDNA) and worse response to AR signaling inhibitors. We also identified topological subtypes associated with stark differences in methylation structure, gene expression and prognosis. Our data suggested that DNA interactions may predispose to structural variant formation, exemplified by the recurrent TMPRSS2-ERG fusion. This comprehensive integrated sequencing effort represents a unique clinical tumor resource.© 2024. The Author(s).