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.
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17 February 2022
A Correction to this paper has been published: https://doi.org/10.1038/s41422-022-00625-x
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Acknowledgements
A special thanks to Mr. Yanhong Li (Baidu) for his generous support of this project. We would like to thank Drs. Y. Shimada (Kyoto University), Enmin Li (Medical College of Shantou University) and Dan Su (Zhejiang Cancer Hospital) for kindly providing cell lines. This study was also supported by funding from the National Key R&D Program of China (2016YFC1302100), the CAMS Innovation Fund for Medical Sciences (2016-I2M-1-001, 2019-I2M-1-003), the National Natural Science Foundation of China (81490753, 81330063, 11971039), the fund of “San-ming” Project of Medicine in Shenzhen (No. SZSM201812088), and the Guangdong Basic and Applied Basic Research Foundation (2019B030302012).
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Z.L., Yanhong L. and Q.Z. supervised the study, designed the experiments, and edited the manuscript. Y.C. supervised all data analyses and experimental studies, and wrote the manuscript. H. Chen, Y. Zhao and F.H. conceived the experimental studies and performed laboratory analyses. H. Chen interpreted the functional results and reviewed the manuscript. Y. Zhao, F.H., Yang L., X.Z. and X.Y. performed the functional experiments. R.X. oversaw the bioinformatics and statistics analyses, interpreted the results and wrote and reviewed the manuscript. H. Cui, Jiawei W., Y. Zhou, W.Z., Jie W. and B.W. provided medical records and survival data, performed bioinformatics analyses, validation of variations, and statistics analyses. T.Y., E.X., X.L., Y.M., S.G., L.Z., Y.X., R.S., B.Y. and X.C. provided clinical samples and data. T.Y., P.K., Y.M., J.L. and B.S. reviewed the histopathology. T.Y., E.X., P.K., Y.M., Y. Liu., F.W., J.Y., H.L., Y.W. and Y. Zhang prepared microneedle-punctured FFPE tissues. Y. Zhai and C.C. performed the immunohistochemistry analyses.
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Cui, Y., Chen, H., Xi, R. et al. Whole-genome sequencing of 508 patients identifies key molecular features associated with poor prognosis in esophageal squamous cell carcinoma. Cell Res 30, 902–913 (2020). https://doi.org/10.1038/s41422-020-0333-6
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DOI: https://doi.org/10.1038/s41422-020-0333-6
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