Research Papers:

The macro-evolutionary events in esophageal squamous cell carcinoma

Bin Yang, Ting Yan, Heyang Cui, Enwei Xu, Yanchun Ma, Caixia Cheng, Ling Zhang, Pengzhou Kong, Fang Wang, Yu Qian, Jian Yang, Yaoping Li, Hongyi Li, Yanghui Bi, Xiaoling Hu, Juan Wang, Bin Song, Jie Yang, Wei Gao, Jing Liu, Binbin Zou, Ruyi Shi, Yanyan Zhang, Haiyan Liu, Yiqian Liu, Yuanfang Zhai, Lu Chang, Yi Wang, Yingchun Zhang, Zhiwu Jia, Xing Chen, Yanfeng Xi, Guodong Li, Jianfang Liang, Jiansheng Guo, Shiping Guo, Rongsheng Zhang, Xiaolong Cheng and Yongping Cui _

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Oncotarget. 2017; 8:112770-112782. https://doi.org/10.18632/oncotarget.22625

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Bin Yang1,2,3,4,*, Ting Yan1,2,3,*, Heyang Cui1,2,3,*, Enwei Xu1,2,3,5,*, Yanchun Ma1,2,3,*, Caixia Cheng1,2,3,6,*, Ling Zhang1,2,3, Pengzhou Kong1,2,3, Fang Wang1,2,3, Yu Qian1,2,3, Jian Yang1,2,3, Yaoping Li1,2,3,7, Hongyi Li1,2,3, Yanghui Bi1,2,3, Xiaoling Hu1,2,3, Juan Wang1,2,3, Bin Song1,2,3, Jie Yang1,2,3, Wei Gao1,2,3, Jing Liu1,8, Binbin Zou1,2,3, Ruyi Shi1,2,3, Yanyan Zhang1,8, Haiyan Liu1,2,3, Yiqian Liu1,2,3, Yuanfang Zhai1,2,3, Lu Chang1,2,3, Yi Wang1,2,3, Yingchun Zhang1,2,3, Zhiwu Jia1,2,3, Xing Chen9, Yanfeng Xi5, Guodong Li5, Jianfang Liang6, Jiansheng Guo8, Shiping Guo4, Rongsheng Zhang4, Xiaolong Cheng1,2,3 and Yongping Cui1,2,3

1Translational Medicine Research Center, Shanxi Medical University, Taiyuan, Shanxi, China

2Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi, China

3Key Laboratory of Cellular Physiology, Ministry of Education, Shanxi Medical University, Taiyuan, Shanxi, China

4Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, China

5Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, China

6Department of Pathology, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China

7Department of Colorectal & Anal Surgery, Shanxi Provincial People’s Hospital, Taiyuan, Shanxi, China

8Department of General Surgery, The First Hospital, Shanxi Medical University, Taiyuan, Shanxi, China

9Department of Endoscopy, Shanxi Cancer Hospital, Taiyuan, Shanxi, China

*These authors have contributed equally to this work

Correspondence to:

Yongping Cui, email: [email protected]

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


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.

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