Research Paper Volume 13, Issue 7 pp 10034—10057

A five-m6A regulatory gene signature is a prognostic biomarker in lung adenocarcinoma patients

Xiao Wu1, *, , Hongxu Sheng1, *, , Luming Wang1, , Pinghui Xia1, , Yiqing Wang1, , Li Yu1, , Wang Lv1, , Jian Hu1, ,

  • 1 Department of Thoracic Surgery, First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, China
* Equal contribution

Received: September 10, 2020       Accepted: January 13, 2021       Published: March 26, 2021
How to Cite

Copyright: © 2021 Wu et al. This is an open access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.


We analyzed the prognostic value of N6-methyladenosine (m6A) regulatory genes in lung adenocarcinoma (LADC) and their association with tumor immunity and immunotherapy response. Seventeen of 20 m6A regulatory genes were differentially expressed in LDAC tissue samples from the TCGA and GEO databases. We developed a five-m6A regulatory gene prognostic signature based on univariate and Lasso Cox regression analysis. Western blot analysis confirmed that the five prognostic m6A regulatory proteins were highly expressed in LADC tissues. We constructed a nomogram with five-m6A regulatory gene prognostic risk signature and AJCC stages. ROC curves and calibration curves showed that the nomogram was well calibrated and accurately distinguished high-risk and low-risk LADC patients. Weighted gene co-expression analysis showed significant correlation between prognostic risk signature genes and the turquoise module enriched with cell cycle genes. The high-risk LADC patients showed significantly higher PD-L1 levels, increased tumor mutational burden, and a lower proportion of CD8+ T cells in the tumor tissues and improved response to immune checkpoint blockade therapy. These findings show that this five-m6A regulatory gene signature is a prognostic biomarker in LADC and that immune checkpoint blockade is a potential therapeutic option for high-risk LADC patients.


ADC: adenocarcinoma; AJCC: American Joint Committee on Cancer; AUC: area under the ROC curve; C-index: concordance index; DCA: decision curve analysis; DEGs: differentially expressed genes; FDR: false discovery rate; GEO: Gene Expression Omnibus; GO: Gene Ontology; GS: Gene significance; GSEA: Gene set enrichment analysis; ICB: immune checkpoint blockade; KEGG: Kyoto Encyclopedia of Genes and Genomes; LASSO: least absolute shrinkage and selection operator; lncRNAs: long non-coding RNAs; m6A: N6-methyladenosine; MEs: Module eigengenes; miRNAs: microRNAs; MM: Module membership; MS: module significance; OS: overall survival; PPI: protein-protein interaction; RCS: restricted cubic splines; ROC: receiver operating characteristic; TCGA: The Cancer Genome Atlas; TIDE: Tumor Immune Dysfunction and Exclusion; TMB: tumor mutational burden; US: United States; WGCNA: Weighted gene co-expression network analysis.