title: Whole-Genome Sequencing Reveals Diverse Models of Structural Variations in Esophageal Squamous Cell Carcinoma.
abstract: Comprehensive identification of somatic structural variations (SVs) and understanding their mutational mechanisms in cancer might contribute to understanding biological differences and help to identify new therapeutic targets. Unfortunately, characterization of complex SVs across the whole genome and the mutational mechanisms underlying esophageal squamous cell carcinoma (ESCC) is largely unclear. To define a comprehensive catalog of somatic SVs, affected target genes, and their underlying mechanisms in ESCC, we re-analyzed whole-genome sequencing (WGS) data from 31 ESCCs using Meerkat algorithm to predict somatic SVs and Patchwork to determine copy-number changes. We found deletions and translocations with NHEJ and alt-EJ signature as the dominant SV types, and 16% of deletions were complex deletions. SVs frequently led to disruption of cancer-associated genes (e.g., CDKN2A and NOTCH1) with different mutational mechanisms. Moreover, chromothripsis, kataegis, and breakage-fusion-bridge (BFB) were identified as contributing to locally mis-arranged chromosomes that occurred in 55% of ESCCs. These genomic catastrophes led to amplification of oncogene through chromothripsis-derived double-minute chromosome formation (e.g., FGFR1 and LETM2) or BFB-affected chromosomes (e.g., CCND1, EGFR, ERBB2, MMPs, and MYC), with approximately 30% of ESCCs harboring BFB-derived CCND1 amplification. Furthermore, analyses of copy-number alterations reveal high frequency of whole-genome duplication (WGD) and recurrent focal amplification of CDCA7 that might act as a potential oncogene in ESCC. Our findings reveal molecular defects such as chromothripsis and BFB in malignant transformation of ESCCs and demonstrate diverse models of SVs-derived target genes in ESCCs. These genome-wide SV profiles and their underlying mechanisms provide preventive, diagnostic, and therapeutic implications for ESCCs.
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of Pathology, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
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authors.affiliation: BGI-Shenzhen, Shenzhen, Guangdong 518083, China.
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authors.lastname: Zhou
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Hongyi
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authors.affiliation: BGI-Shenzhen, Shenzhen, Guangdong 518083, China.
authors.forename: Teng
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authors.lastname: Xiong
authors.affiliation: Department of Computer Science, City University of Hong Kong, Hong Kong 518057, China.
authors.forename: Shuaicheng
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Yanghui
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authors.lastname: Bi
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Pengzhou
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authors.lastname: Kong
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Fang
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China; BGI-Shenzhen, Shenzhen, Guangdong 518083, China.
authors.forename: Heyang
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authors.lastname: Cui
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, China.
authors.forename: Yaoping
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authors.lastname: Li
authors.affiliation: BGI-Shenzhen, Shenzhen, Guangdong 518083, China.
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Yan
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of General Surgery, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Yike
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Yang
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
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authors.initials: L
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
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authors.initials: Z
authors.lastname: Jia
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of Oncology, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Bin
authors.initials: B
authors.lastname: Song
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Xiaoling
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
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authors.forename: Ruyi
authors.initials: R
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of General Surgery, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Yanyan
authors.initials: Y
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Haiyan
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Zhenxiang
authors.initials: Z
authors.lastname: Zhao
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Yu
authors.initials: Y
authors.lastname: Qian
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of General Surgery, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Ruizhou
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authors.lastname: Rong
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Department of General Surgery, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Zhiwei
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authors.affiliation: Department of Computer Science, City University of Hong Kong, Hong Kong 518057, China.
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authors.forename: Jiaqian
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authors.affiliation: School of Computer Science & State Key Laboratory of High Performance Computing National University of Defense Technology, Changsha, Hunan 410073, China.
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authors.affiliation: Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, China.
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authors.affiliation: Department of Endoscopy, Shanxi Provincial People's Hospital, Taiyuan, Shanxi 030001, China.
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authors.affiliation: Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, China.
authors.forename: Yanfeng
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authors.affiliation: Department of Urology, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
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authors.affiliation: Department of General Surgery, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
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authors.affiliation: Department of Oncology, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: JunMei
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authors.lastname: Jia
authors.affiliation: School of Pharmaceutical Sciences, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Qingshan
authors.initials: Q
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authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China.
authors.forename: Xiaolong
authors.initials: X
authors.lastname: Cheng
authors.affiliation: State Key Laboratory of Molecular Oncology, Cancer Institute and Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China. Electronic address: zhanqimin@pumc.edu.cn.
authors.forename: Qimin
authors.initials: Q
authors.lastname: Zhan
authors.affiliation: Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi 030001, China; Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi 030001, China. Electronic address: cuiy0922@yahoo.com.
authors.forename: Yongping
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authors.lastname: Cui
mesh_terms: D002294:Carcinoma, Squamous Cell / Q000235:genetics*; D002460:Cell Line; D019938:Cyclin D1 / Q000235:genetics; D056915:DNA Copy Number Variations; D066246:ErbB Receptors / Q000235:genetics; D004938:Esophageal Neoplasms / Q000235:genetics*; D000077277:Esophageal Squamous Cell Carcinoma; D017353:Gene Deletion; D015321:Gene Rearrangement; D019942:Genes, p16; D056726:Genetic Association Studies / Q000379:methods*; D014644:Genetic Variation; D015894:Genome, Human; D023281:Genomics; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D051881:Receptor, Notch1 / Q000235:genetics; D015203:Reproducibility of Results; D017423:Sequence Analysis, RNA; D014178:Translocation, Genetic
chemical_list: D019938:Cyclin D1; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; D051881:Receptor, Notch1; C530104:CCND1 protein, human; C497761:NOTCH1 protein, human; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C496348:FGFR1 protein, human
keywords: ESCC; breakage-fusion-bridge; chromothripsis; structural variation; whole-genome duplication
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