As a major type of structural variants, tandem duplication plays a critical role in tumorigenesis by increasing oncogene dosage. Recent work has revealed that noncoding enhancers are also affected by duplications leading to the activation of oncogenes that are inside or outside of the duplicated regions. However, the prevalence of enhancer duplication and the identity of their target genes remains largely unknown in the cancer genome. Here, by analyzing whole-genome sequencing data in a non-gene-centric manner, we identify 881 duplication hotspots in 13 major cancer types, most of which do not contain protein-coding genes. We show that the hotspots are enriched with distal enhancer elements and are highly lineage-specific. We develop a HiChIP-based methodology that navigates enhancer–promoter contact maps to prioritize the target genes for the duplication hotspots harboring enhancer elements. The methodology identifies many novel enhancer duplication events activating oncogenes such as ESR1, FOXA1, GATA3, GATA6, TP63, and VEGFA, as well as potentially novel oncogenes such as GRHL2, IRF2BP2, and CREB3L1. In particular, we identify a duplication hotspot on Chromosome 10p15 harboring a cluster of enhancers, which skips over two genes, through a long-range chromatin interaction, to activate an oncogenic isoform of the NET1 gene to promote migration of gastric cancer cells. Focusing on tandem duplications, our study substantially extends the catalog of noncoding driver alterations in multiple cancer types, revealing attractive targets for functional characterization and therapeutic intervention.

中文翻译：

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染色质相互作用图可识别癌症中增强子重复的致癌靶点


作为一种主要的结构变异类型，串联复制通过增加癌基因剂量在肿瘤发生中起关键作用。最近的工作表明，非编码增强子也受到重复的影响，导致复制区域内部或外部的癌基因激活。然而，增强子复制的普遍性及其靶基因的身份在癌症基因组中在很大程度上仍然未知。在这里，通过以非基因为中心的方式分析全基因组测序数据，我们在 13 种主要癌症类型中鉴定了 881 个重复热点，其中大多数不包含蛋白质编码基因。我们表明热点富含远端增强子元件，并且具有高度谱系特异性。我们开发了一种基于 HiChIP 的方法，该方法导航增强子-启动子接触图谱，以优先考虑含有增强子元件的复制热点的目标基因。该方法确定了许多激活癌基因（如 ESR1、FOXA1、GATA3、GATA6、TP63 和 VEGFA）的新型增强子复制事件，以及潜在的新型癌基因（如 GRHL2、IRF2BP2 和 CREB3L1）。特别是，我们在染色体 10p15 上鉴定了一个复制热点，该热点含有一簇增强子，该增强子通过长程染色质相互作用跳过两个基因，以激活 NET1 基因的致癌亚型，以促进胃癌细胞的迁移。我们的研究专注于串联重复，大大扩展了多种癌症类型中非编码驱动因素改变的目录，揭示了功能表征和治疗干预的有吸引力的靶点。