Characterization of somatic structural variations in 528 Chinese individuals with Esophageal squamous cell carcinoma

Heyang Cui, Yong Zhou, Fang Wang, Caixia Cheng, Weimin Zhang, Ruifang Sun, Ling Zhang, Yanghui Bi, Min Guo, Yan Zhou, Xinhui Wang, Jiaxin Ren, Ruibing Bai, Ning Ding, Chen Cheng, Longlong Wang, Xuehan Zhuang, Mingwei Gao, Yongjia Weng, Yueguang Wu, Huijuan Liu, Shuaicheng Li, Shubin Wang, Xiaolong Cheng, Yongping Cui (), Zhihua Liu () and Qimin Zhan ()
Additional contact information
Heyang Cui: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Yong Zhou: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Fang Wang: Shanxi Medical University
Caixia Cheng: The First Hospital, Shanxi Medical University
Weimin Zhang: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Ruifang Sun: Shanxi Provincial Cancer Hospital
Ling Zhang: Shanxi Medical University
Yanghui Bi: Shanxi Medical University
Min Guo: Shanxi Medical University
Yan Zhou: Shanxi Medical University
Xinhui Wang: Shanxi Medical University
Jiaxin Ren: The First Hospital, Shanxi Medical University
Ruibing Bai: The First Hospital, Shanxi Medical University
Ning Ding: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Chen Cheng: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Longlong Wang: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Xuehan Zhuang: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Mingwei Gao: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Yongjia Weng: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Yueguang Wu: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Huijuan Liu: Shanxi Medical University
Shuaicheng Li: City University of Hong Kong Shenzhen Research Institute
Shubin Wang: Peking University Shenzhen Hospital, Shenzhen-Peking University-Hong Kong University of Science and Technology Medical Center
Xiaolong Cheng: Shanxi Medical University
Yongping Cui: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory
Zhihua Liu: Chinese Academy of Medical Sciences and Peking Union Medical College
Qimin Zhan: Peking University Shenzhen Hospital, Shenzhen Peking University-the Hong Kong University of Science and Technology (PKU-HKUST) Medical Center; Institute of Cancer Research, Shenzhen Bay Laboratory

Nature Communications, 2022, vol. 13, issue 1, 1-18

Abstract: Abstract Esophageal squamous cell carcinoma (ESCC) demonstrates high genome instability. Here, we analyze 528 whole genomes to investigate structural variations’ mechanisms and biological functions. SVs show multi-mode distributions in size, indicating distinct mutational processes. We develop a tool and define five types of complex rearrangements with templated insertions. We highlight a type of fold-back inversion, which is associated with poor outcomes. Distinct rearrangement signatures demonstrate variable genomic metrics such as replicating time, spatial proximity, and chromatin accessibility. Specifically, fold-back inversion tends to occur near the centrosome; TD-c2 (Tandem duplication-cluster2) is significantly enriched in chromatin-accessibility and early-replication region compared to other signatures. Analyses of TD-c2 signature reveal 9 TD hotspots, of which we identify a hotspot consisting of a super-enhancer of PTHLH. We confirm the oncogenic effect of the PTHLH gene and its interaction with enhancers through functional experiments. Finally, extrachromosomal circular DNAs (ecDNAs) are present in 14% of ESCCs and have strong selective advantages to driver genes.

Date: 2022
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DOI: 10.1038/s41467-022-33994-3

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