PDF(Pubmed)
Abstract：
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.
摘要：
基因组三维结构变异的影响已被认识到,但实体癌组织研究是有限的。这里,我们进行了整合的深度Hi-C测序与匹配的全基因组测序，全基因组亚硫酸氢盐测序，来自转移性去势抵抗性前列腺癌患者的80个活检样本的队列中的5-羟甲基胞嘧啶(5hmC)测序和RNA测序。基因表达存在巨大差异，5-甲基胞嘧啶/5hmC甲基化和结构变异与A和B(开放和封闭)染色质区室之间的突变率。一部分肿瘤在AR位点表现出耗尽的区域染色质接触，与染色体外环状DNA（ecDNA）相关，对AR信号传导抑制剂的反应较差。我们还确定了与甲基化结构明显差异相关的拓扑亚型，基因表达和预后。我们的数据表明，DNA相互作用可能导致结构变体形成，以复发性TMPRSS2-ERG融合为例。这种全面的整合测序工作代表了独特的临床肿瘤资源。
