作为结构变异的主要类型，串联重复通过增加癌基因剂量在肿瘤发生中发挥关键作用。最近的研究表明，非编码增强子也受到重复的影响，导致重复区域内部或外部的癌基因被激活。然而，癌症基因组中增强子重复的普遍程度及其靶基因的身份仍然很大程度上未知。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 种主要癌症类型中识别出 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，该方法可导航增强子-启动子接触图，以优先考虑包含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的新增强子重复事件，如 ESR1、FOXA1、GATA3、GATA6、TP63 和 VEGFA，以及潜在的新癌基因，如 GRHL2、IRF2BP2 和 CREB3L1。特别是，我们确定了染色体 10p15 上的重复热点含有一组增强子，通过长程染色质相互作用跳过两个基因，激活 NET1 基因的致癌异构体，从而促进胃癌细胞的迁移。我们的研究重点关注串联重复，大大扩展了多种癌症类型中非编码驱动改变的目录，揭示了功能表征和治疗干预的有吸引力的目标。© 2024 Song et al.；由冷泉港实验室出版社出版。

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.© 2024 Song et al.; Published by Cold Spring Harbor Laboratory Press.