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

• Published in: Nature communications 2022-10, Vol.13 (1), p.6296-18, Article 6296
• Main Authors: Cui, Heyang, Zhou, Yong, Wang, Fang, Cheng, Caixia, Zhang, Weimin, Sun, Ruifang, Zhang, Ling, Bi, Yanghui, Guo, Min, Zhou, Yan, Wang, Xinhui, Ren, Jiaxin, Bai, Ruibing, Ding, Ning, Cheng, Chen, Wang, Longlong, Zhuang, Xuehan, Gao, Mingwei, Weng, Yongjia, Wu, Yueguang, Liu, Huijuan, Li, Shuaicheng, Wang, Shubin, Cheng, Xiaolong, Cui, Yongping, Liu, Zhihua, Zhan, Qimin
• Format: Article
• Language: English
• Subjects: 13/51; 13/89; 14/32; 38/23; 38/43; 38/91; 631/208/514/1948; 631/208/69; 631/67/1504/1477; 631/67/395; 692/308/2056; Accessibility; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - pathology; China; Chromatin; Chromatin - genetics; DNA, Circular; Enhancers; Esophageal cancer; Esophageal Neoplasms - genetics; Esophageal Neoplasms - pathology; Esophageal Squamous Cell Carcinoma - genetics; Esophagus; Genomes; Genomic instability; Humanities and Social Sciences; Humans; Inversion; Molecular modelling; multidisciplinary; Science; Science (multidisciplinary); Signatures; Squamous cell carcinoma; Stability analysis; Structural analysis; Variation
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-022-33994-3

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. The biological and clinical implications of high genome instability in esophageal squamous cell carcinoma (ESCC) remain to be explored. Here, the authors analyse 528 whole genomes and investigate the landscape and molecular mechanisms underlying structural variations in ESCC patients.