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

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.

• Authors: Yongping Cui, Hongyan Chen, Ruibin Xi, Heyang Cui, Yahui Zhao, Enwei Xu, Ting Yan, Xiaomei Lu, Furong Huang, Pengzhou Kong, Yang Li, Xiaolin Zhu, Jiawei Wang, Wenjie Zhu, Jie Wang, Yanchun Ma, Yong Zhou, Shiping Guo, Ling Zhang, Yiqian Liu, Bin Wang, Yanfeng Xi, Ruifang Sun, Xiao Yu, Yuanfang Zhai, Fang Wang, Jian Yang, Bin Yang, Caixia Cheng, Jing Liu, Bin Song, Hongyi Li, Yi Wang, Yingchun Zhang, Xiaolong Cheng, Qimin Zhan, Yanhong Li, Zhihua Liu
• Journal: Cell research (Cell Res) Vol. 30 Issue 10 Pg. 902-913 (10 2020) ISSN: 1748-7838 [Electronic] England
• PMID: 32398863 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers, Tumor
• Membrane Transport Proteins
• NF-E2-Related Factor 2
• NFE2L2 protein, human
• Nerve Tissue Proteins
• SLC35F1 protein, human

Topics

• Adult
• Aged
• Biomarkers, Tumor (genetics)
• Cohort Studies
• Esophageal Neoplasms (genetics)
• Esophageal Squamous Cell Carcinoma (genetics)
• Female
• Gene Expression Regulation, Neoplastic
• Genes, Tumor Suppressor
• Humans
• Male
• Membrane Transport Proteins (genetics)
• Middle Aged
• Mutation
• NF-E2-Related Factor 2 (genetics)
• Nerve Tissue Proteins (genetics)
• Prognosis
• Promoter Regions, Genetic