Volume 30, No 10, Oct 2020

ISSN: 1001-0602 
EISSN: 1748-7838 2018 
impact factor 17.848* 
(Clarivate Analytics, 2019)

Volume 30 Issue 10, October 2020: 902-913

ORIGINAL ARTICLES

Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma

Yongping Cui^1,† , Hongyan Chen^2,† , Ruibin Xi^3,† , Heyang Cui^4,5,† , Yahui Zhao^2,† , Enwei Xu^1,6,† , Ting Yan¹ , Xiaomei Lu⁷ , Furong Huang² , Pengzhou Kong¹ , Yang Li² , Xiaolin Zhu² , Jiawei Wang⁸ , Wenjie Zhu⁸ , Jie Wang⁸ , Yanchun Ma¹ , Yong Zhou^1,5 , Shiping Guo⁹ , Ling Zhang^1,5 , Yiqian Liu^1,5 , Bin Wang⁵ , Yanfeng Xi⁶ , Ruifang Sun¹⁰ , Xiao Yu² , Yuanfang Zhai^1,5 , Fang Wang¹ , Jian Yang¹ , Bin Yang^1,9 , Caixia Cheng^1,11 , Jing Liu¹ , Bin Song¹ , Hongyi Li¹ , Yi Wang^1,5 , Yingchun Zhang^1,5 , Xiaolong Cheng¹ , Qimin Zhan^4,5,* , Yanhong Li^1,2,* , Zhihua Liu^2,*

¹Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi 030001, China;
²State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China;
³School of Mathematical Sciences, Center for Statistical Science and Department of Biostatistics, Peking University, Beijing 100871, China;
⁴Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing 100142, China;
⁵Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, Guangdong 518035, China;
⁶Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, China;
⁷Tumor Hospital affiliated to Xinjiang Medical University, Urumqi, Xinjiang 830011, China;
⁸WuXi NextCODE, Shanghai 200131, China;
⁹Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, China;
¹⁰Tumor Biobank, Shanxi Cancer Hospital, Taiyuan, Shanxi 030001, China;
¹¹Department of Pathology, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi 030001, China
¹²Baidu, Beijing 100085, China
^†These authors contributed equally
Correspondence: Qimin Zhan(zhanqimin@bjmu.edu.cn)Yanhong Li(robin@baidu.com)Zhihua Liu(liuzh@cicams.ac.cn)

Esophageal squamous cell carcinoma (ESCC) is a poor-prognosis cancer type with limited understanding of its molecular etiology. Using 508 ESCC genomes, we identified five novel significantly mutated genes and uncovered mutational signature clusters associated with metastasis and patients’ outcomes. Several functional assays implicated that NFE2L2 may act as a tumor suppressor in ESCC and that mutations in NFE2L2 probably impaired its tumor-suppressive function, or even conferred oncogenic activities. Additionally, we found that the NFE2L2 mutations were significantly associated with worse prognosis of ESCC. We also identified potential noncoding driver mutations including hotspot mutations in the promoter region of SLC35E2 that were correlated with worse survival. Approximately 5.9% and 15.2% of patients had high tumor mutation burden or actionable mutations, respectively, and may benefit from immunotherapy or targeted therapies. We found clinically relevant coding and noncoding genomic alterations and revealed three major subtypes that robustly predicted patients’ outcomes. Collectively, we report the largest dataset of genomic profiling of ESCC useful for developing ESCC-specific biomarkers for diagnosis and treatment.

https://doi.org/10.1038/s41422-020-0333-6

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