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Identification of A-to-I RNA editing profiles and their clinical relevance in lung adenocarcinoma

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Abstract

Adenosine-to-inosine (A-to-I) RNA editing is a widespread posttranscriptional modification that has been shown to play an important role in tumorigenesis. Here, we evaluated a total of 19,316 RNA editing sites in the tissues of 80 lung adenocarcinoma (LUAD) patients from our Nanjing Lung Cancer Cohort (NJLCC) and 486 LUAD patients from the TCGA database. The global RNA editing level was significantly increased in tumor tissues and was highly heterogeneous across patients. The high RNA editing level in tumors was attributed to both RNA (ADAR1 expression) and DNA alterations (mutation load). Consensus clustering on RNA editing sites revealed a new molecular subtype (EC3) that was associated with the poorest prognosis of LUAD patients. Importantly, the new classification was independent of classic molecular subtypes based on gene expression or DNA methylation. We further proposed a simplified model including eight RNA editing sites to accurately distinguish the EC3 subtype in our patients. The model was further validated in the TCGA dataset and had an area under the curve (AUC) of the receiver operating characteristic curve of 0.93 (95%CI: 0.91–0.95). In addition, we found that LUAD cell lines with the EC3 subtype were sensitive to four chemotherapy drugs. These findings highlighted the importance of RNA editing events in the tumorigenesis of LUAD and provided insight into the application of RNA editing in the molecular subtyping and clinical treatment of cancer.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (81922061, 82072579, 81521004, 81973123 and 81871885), the National Key Research and Development Project (2017YFC0907905), and Research Unit of Prospective Cohort of Cardiovascular Diseases and Cancer, Chinese Academy of Medical Sciences (2019RU038). We are grateful to the patients who participated in this study and all the researchers, clinicians and technical and administrative staff who have made this work possible.

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Authors and Affiliations

  1. Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China

    Cheng Wang, Mingtao Huang, Congcong Chen, Yuancheng Li, Na Qin, Zijian Ma, Jingyi Fan, Linnan Gong, Liu Yang, Xianfeng Xu, Jun Zhou, Juncheng Dai, Guangfu Jin, Zhibin Hu, Hongxia Ma & Hongbing Shen

  2. Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personized Medicine, Nanjing Medical University, Nanjing, 211166, China

    Cheng Wang, Mingtao Huang, Congcong Chen, Yuancheng Li, Na Qin, Zijian Ma, Jingyi Fan, Linnan Gong, Liu Yang, Xianfeng Xu, Jun Zhou, Juncheng Dai, Guangfu Jin, Zhibin Hu, Hongxia Ma & Hongbing Shen

  3. Department of Thoracic Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Hui Zeng & Fengwei Tan

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  1. Cheng Wang
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Correspondence to Hongxia Ma, Fengwei Tan or Hongbing Shen.

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Compliance and ethics The author(s) declare that they have no conflict of interest. All participants signed an informed consent form that was approved by the local internal review boards or ethics committees (Nanjing, China).

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Wang, C., Huang, M., Chen, C. et al. Identification of A-to-I RNA editing profiles and their clinical relevance in lung adenocarcinoma. Sci. China Life Sci. 65, 19–32 (2022). https://doi.org/10.1007/s11427-020-1928-0

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