Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma
Authors: Jie Wang
Hongyan Chen
Wenjie Zhu
Furong Huang
Yong Zhou
Shiping Guo
Jiawei Wang
Yiqian Liu
Ruifang Sun
Bin Song
Heyang Cui
Yahui Zhao
Yi Wang
Fang Wang
Xiaolin Zhu
Xiaomei Lu
Yanfeng Xi
Ruibin Xi
Caixia Cheng
Xiao Yu
Yang Li
Yingchun Zhang
Yongping Cui
Ling Zhang
Jing Liu
Zhihua Liu
Hongyi Li
Bin Wang
Yuanfang Zhai
Enwei Xu
Yanchun Ma
Pengzhou Kong
Xiaolong Cheng
Yanhong Li
Jian Yang
Bin Yang
Qimin Zhan
Ting Yan
Journal: Cell Research (2020)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: Esophageal squamous cell carcinoma; molecular etiology; significantly mutated genes; mutational signature clusters; metastasis
Affiliations: Department of Pathology & Shanxi Key Laboratory of Carcinogenesis and Translational Research on Esophageal Cancer, Shanxi Medical University, Taiyuan, Shanxi, 030001, China., State 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., School of Mathematical Sciences, Center for Statistical Science and Department of Biostatistics, Peking University, Beijing, 100871, China., Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China., Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, Guangdong, 518035, China., Department of Pathology, Shanxi Cancer Hospital, Taiyuan, Shanxi, 030001, China., Tumor Hospital affiliated to Xinjiang Medical University, Urumqi, Xinjiang, 830011, China., WuXi NextCODE, Shanghai, 200131, China., Department of Tumor Surgery, Shanxi Cancer Hospital, Taiyuan, Shanxi, 030001, China., Tumor Biobank, Shanxi Cancer Hospital, Taiyuan, Shanxi, 030001, China., Department of Pathology, the First Hospital, Shanxi Medical University, Taiyuan, Shanxi, 030001, China., Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Molecular Oncology, Peking University Cancer Hospital & Institute, Beijing, 100142, China. ., Cancer Institute, Peking University Shenzhen Hospital, Shenzhen Peking University-The Hong Kong University of Science and Technology (PKU-HKUST) Medical Center, Shenzhen, Guangdong, 518035, China. ., Baidu, Beijing, 100085, China. ., State 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. .

Abstract:  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. 

Retracted: No

PubPeer comments:
 In sTable1 and sTable5, the sample ID of BDESCC-01-838 was duplicated in two rows. In sTable1 the TMB values of the two patients were all 5.74. ![file] However, in sTable5, the two samples were apparently different in number of SNVs, the BDESCC-01-838 of Taihang presented much higher mutation load than the other. ![file] Hope the authors chould check and correct this error. , 
 #1 Thank you very much for your careful reading. We have noticed the error and have contacted the editorial office and now waiting for the correction. In our study, we have de-identified patient details and re-numbered the sample ID using random number (between 1 and 1000) generated by Excel such that the identity of any person may not be ascertained in any way. For example, sample ID BDESCC-01-838, BDESCC-01 is our project ID and 838 is the random number generated by Excel. Unfortunately, the random number generated by Excel generates duplicates and two 838 were generated and assigned to two different patients: BDESCC0585 and BDESCC0671(Figure 1). However, the random ID didnu2019t affect the original ID and the original information of the patient, thus, the error doesnu2019t affect our results and conclusions. ![file] Figure 1. The original sample id of BDESCC-01-838. BDESCC0585 has also duplicated the BDESCC0671u2019s TMB value in this table, the actual TMB of BDESCC0585 is 3.61, which is reasonable for its total SNV InDel number. We have re-examined all sample ID, and that is the only sample affected by this Excel random number isssue. We apologize for the error, and we have contacted the editor to correct the sample ID. Thanks again. Zhihua Liu ,