TY  - JOUR
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
Y1  - 2024/10/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 1514 
EP  - 1527 
DO  - 10.1101/gr.278418.123 
VL  - 34 
IS  - 10 
UR  - http://genome.cshlp.org/content/34/10/1514.abstract 
N2  - 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. 
ER  -