The macro-evolutionary events in esophageal squamous cell carcinoma

// Bin Yang 1, 2, 3, 4, * , Ting Yan 1, 2, 3, * , Heyang Cui 1, 2, 3, * , Enwei Xu 1, 2, 3, 5, * , Yanchun Ma 1, 2, 3, * , Caixia Cheng 1, 2, 3, 6, * , Ling Zhang 1, 2, 3 , Pengzhou Kong 1, 2, 3 , Fang Wang 1, 2, 3 , Yu Qian 1, 2, 3 , Jian Yang 1, 2, 3 , Yaoping Li 1, 2, 3, 7 , Hongyi Li 1, 2, 3 , Yanghui Bi 1, 2, 3 , Xiaoling Hu 1, 2, 3 , Juan Wang 1, 2, 3 , Bin Song 1, 2, 3 , Jie Yang 1, 2, 3 , Wei Gao 1, 2, 3 , Jing Liu 1, 8 , Binbin Zou 1, 2, 3 , Ruyi Shi 1, 2, 3 , Yanyan Zhang 1, 8 , Haiyan Liu 1, 2, 3 , Yiqian Liu 1, 2, 3 , Yuanfang Zhai 1, 2, 3 , Lu Chang 1, 2, 3 , Yi Wang 1, 2, 3 , Yingchun Zhang 1, 2, 3 , Zhiwu Jia 1, 2, 3 , Xing Chen 9 , Yanfeng Xi 5 , Guodong Li 5 , Jianfang Liang 6 , Jiansheng Guo 8 , Shiping Guo 4 , Rongsheng Zhang 4 , Xiaolong Cheng 1, 2, 3 and Yongping Cui 1, 2, 3 1 Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China 2 Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi, China 3 Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China 4 Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China 5 Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China 6 Department of Pathology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China 7 Department of Colorectal & Anal Surgery, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, China 8 Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China 9 Department of Endoscopy, Shanxi Cancer Hospital, Taiyuan, Shanxi, China * These authors have contributed equally to this work Correspondence to: Yongping Cui, email: cuiyp@sxmu.edu.cn Keywords: esophageal squamous cell carcinoma (ESCC); whole genome doubling (WGD); neutral loss of heterozygosity (NLOH); telomere-bounded copy number alterations (TCNAs); genome evolution Received: July 28, 2017     Accepted: October 28, 2017     Published: November 15, 2017 ABSTRACT Understanding the evolutionary processes operative in cancer genome may provide insights into clinical outcome and drug-resistance. However, studies focus on genomic signatures, especially for macro-evolutionary events, in esophageal squamous cell carcinoma (ESCC) are limited. Here, we integrated published genomic sequencing data to investigate underlying evolutionary characteristics in ESCC. We found most of ESCC genomes were polyploidy with high genomic instability. Whole genome doubling that acts as one of mechanisms for polyploidy was predicted as a late event in the majority of ESCC genome. Moreover, loss of heterozygosity events were more likely to occur in chromosomes harboring tumor suppressor genes in ESCC. The 40% of neutral loss of heterozygosity events was not a result of genome doubling, suggesting an alternative mechanism for neutral loss of heterozygosity formation. Importantly, deconstruction of copy number alterations extending to telomere revealed that telomere-bounded copy number alterations play a critical role for amplification/deletion of oncogenes/suppressor genes. For well-known genes SOX2 , PIK3CA and TERT , nearly all of their amplifications were telomere bounded, which was further confirmed in a Japanese ESCC cohort. Furthermore, we provide evidence that karyotype evolution was mostly punctuated in ESCC. Collectively, our data reveal the potential biological role of whole genome doubling, neutral loss of heterozygosity and telomere-bounded copy number alterations, and highlight mecro-evolution in ESCC tumorigenesis.