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©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.
Integrated single-cell and bulk RNA sequencing revealed an epigenetic signature predicts prognosis and tumor microenvironment colorectal cancer heterogeneity
Han-Xuan Liu, Jie Feng, Jing-Jing Jiang, Wan-Jun Shen, Yu Zheng, Gang Liu, Xiang-Yang Gao
Han-Xuan Liu, Beijing Jinghua Anliang Technology, Beijing 102627, China
Jie Feng, Department of Clinical Laboratory, The First Medical Centre of Chinese PLA General Hospital, Beijing 100853, China
Jing-Jing Jiang, Clinical Biological Sample Center, Medical Innovation Research Division of Chinese PLA General Hospital, Beijing 100853, China
Wan-Jun Shen, Department of Nephrology, The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
Yu Zheng, Gang Liu, Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China
Xiang-Yang Gao, The Second Medical Center and National Clinical Research Center for Geriatric Diseases, Chinese PLA General Hospital, Beijing 100853, China
Co-first authors: Han-Xuan Liu and Jie Feng.
Co-corresponding authors: Gang Liu and Xiang-Yang Gao.
Author contributions: Liu HX contributed to the interpretation and revising of the manuscript, as well as conceptualization; Feng J and Jiang JJ participated in investigation, data curation, and planning. Both Feng J and Jiang JJ were involved in writing the manuscript, and in further study project planning and advising. Liu G and Gao XY contributed to conceptualization, data curation, formal analysis, investigation, methodology, administration, validation, visualization, and manuscript writing. Zheng Y was involved in data curation, investigation, and visualization. All authors participated in manuscript writing and revising. Liu HX and Feng J contributed equally to this work for three reasons: Firstly, Liu HX and Feng J wrote most of the new parts of the manuscript and interpreted the data. In addition, the manuscript was primarily based on the results analyzed by them, and they devoted the most time among the authors. Liu G and Gao XY, who are designated as co-corresponding authors, designed the study based on their interests. All processes in this study were administered under their supervision. Moreover, they provided invaluable opinions during manuscript writing and revision. In summary, Liu HX and Feng J qualify as co-first authors, while Liu G and Gao XY qualify as co-corresponding authors.
Conflict-of-interest statement: All the authors report no relevant conflicts of interest for this article.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See:
https://creativecommons.org/Licenses/by-nc/4.0/ Corresponding author: Gang Liu, PhD, Academic Fellow, Assistant Professor, Institute of Biomedical Sciences, Fudan University, No. 131 Dongan Road, Shanghai 200032, China. liugang@fudan.edu.cn
Received: February 18, 2024
Revised: April 23, 2024
Accepted: May 7, 2024
Published online: July 15, 2024
Processing time: 145 Days and 12.7 Hours
BACKGROUND
Colorectal cancer (CRC) prognosis prediction is currently a major challenge. Epigenetic regulation has been widely reported for its role in cancer development.
AIM
To construct a robust prognostic signature, we used developed and validated across datasets.
METHODS
After constructing the signature, the prognostic value of the signature was evaluated in the TCGA cohort and six independent datasets (GSE17526, GSE17537, GSE33113, GSE37892, GSE39048 and GSE39582). The clinical, genomic and transcriptomic features related to the signature were identified. The correlations of the signature score with immune cell infiltration and cell-cell interactions were analyzed. The correlations between the signature score and the sensitivity to different drugs were also predicted.
RESULTS
In the TCGA cohort, patients in the low-risk group according to the signature score had longer survival than those in the high-risk group, and this finding was validated in the validation datasets. The signature was a prognostic factor independent of age and sex and was correlated with stage and PD-1/PD-L1 expression. Area under the receiving operating characteristic curve was 0.72. Genomic association analyses revealed that samples from high-risk patients exhibited chromosomal instability. Transcriptomic analyses revealed that the signature score was significantly associated with multiple cellular pathways. Bulk RNA-seq and single-cell sequencing data revealed that the signature reflected differences in infiltrating immune cell-tumor cell interactions, especially for macrophages. The signature also predicted the putative drug sensitivity of CRC samples.
CONCLUSION
The signature is a valuable biomarker for predicting CRC prognosis and reflects multiple features of CRC, especially macrophage infiltration in the microenvironment.
Core Tip: Epigenetic regulation has been widely reported to play a role in colorectal cancer (CRC). In this work, a prognostic signature of epigenetically regulated genes was constructed and validated. The signature reflects various biological features of CRC, especially the microenvironment. It also has outstanding performance for CRC prognosis prediction.
