Molecular features, biological behaviors and clinical implications of m5C RNA methylation modification regulators in gastrointestinal cancers

Mengyao Zhan; Huan Song; Dan Tian; Qin Wen; Xinling Shi; Yuting Wang; Xuhua Mao; Jianming Wang

doi:10.1080/15384047.2023.2223382

Molecular features, biological behaviors and clinical implications of m⁵C RNA methylation modification regulators in gastrointestinal cancers

Cancer Biol Ther. 2023 Dec 31;24(1):2223382. doi: 10.1080/15384047.2023.2223382.

Authors

Mengyao Zhan¹, Huan Song^{1

2}, Dan Tian¹, Qin Wen¹, Xinling Shi¹, Yuting Wang¹, Xuhua Mao³, Jianming Wang¹

Affiliations

¹ Department of Epidemiology, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, China.
² Department of Occupational Health, Suzhou Center for Disease Control and Prevention, Suzhou, China.
³ Department of Clinical Laboratory, Yixing People's Hospital, Wuxi, China.

Abstract

Epitranscriptome studies have shown that critical RNA modifications drive tumorigenicity; however, the role of 5-methylcytosine (m⁵C) RNA methylation remains poorly understood. We extracted 17 m⁵C regulators and clustered distinct m⁵C modification patterns by consensus clustering analysis. Gene set variation and single-sample gene set enrichment analysis were applied to quantify functional analysis and immune infiltration. The least absolute shrinkage and selection operator was employed to develop a prognostic risk score. Kaplan-Meier with log-rank test was used for survival analysis. Differential expression analysis was performed with the "limma" R package. Wilcoxon signed ranked test or Kruskal-Wallis test was used to compare groups. We observed that m⁵C RNA methylation was commonly upregulated in gastrointestinal cancer and related to prognosis. Clusters were identified for m⁵C patterns, with distinct immune infiltrations and functional pathways. The risk scores of m⁵C regulators were independent risk factors. Differentially expressed mRNAs (DEmRNAs) in m⁵C clusters were involved in cancer-related pathways. The methylation-based m⁵Cscore showed a significant effect on the prognosis. Patients with a lower m⁵Cscore exhibited more therapeutic efficiency on anti-CTLA4 therapy in liver cancer, while the combination of anti-CTLA4 therapy and pd1 was more efficient for patients with a lower m⁵Cscore in pancreatic cancer. We uncovered dysregulations of m⁵C-related regulators in gastrointestinal cancer and their associations with overall survival. Some immune cells were differently infiltrated in distinct m⁵C modification patterns, indicating their potential impacts on gastrointestinal cancer cell-immune. Moreover, an m⁵Cscore, derived from DEmRNAs in specific clusters, can serve as a classifier for immunotherapy.

Keywords: 5-methylcytosine; Epigenetics; gastrointestinal cancer; immunotherapy; methylation; prognostic biomarker; transcriptome.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Gastrointestinal Neoplasms* / genetics
Humans
Liver Neoplasms*
Methylation
Pancreatic Neoplasms*
Prognosis
RNA

Substances

RNA

Grants and funding

The present work was financially supported by the National Natural Science Foundation of China (82173595, 81673249), the Postgraduate Research & Practice Innovation Program of Jiangsu Province (KYCX20_1411), and Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD). The funding agencies had no role in the study design, data collection, analysis, publication decision, or manuscript preparation.