RT Journal
A1 Song, Yueqiang
A1 Li, Fuyuan
A1 Wang, Shangzi
A1 Wang, Yuntong
A1 Lai, Cong
A1 Chen, Lian
A1 Jiang, Ning
A1 Li, Jin
A1 Chen, Xingdong
A1 Bailey, Swneke D.
A1 Zhang, Xiaoyang
T1 Chromatin interaction maps identify oncogenic targets of enhancer duplications in cancer
JF Genome Research 
JO Genome Research 
YR 2024 
FD October 01 
VO 34 
IS 10 
SP 1514 
OP 1527 
DO 10.1101/gr.278418.123 
UL http://genome.cshlp.org/content/34/10/1514.abstract 
AB 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.