A new risk model based on a 11-m ⁶A-related lncRNA signature for predicting prognosis and monitoring immunotherapy for gastric cancer

Abstract

Objective

N ⁶-methyladenosine (m ⁶A) mRNA modification triggers malignant behaviors of tumor cells and thereby drives malignant progression in gastric cancer (GC). However, data regarding the prognostic values of m ⁶A RNA methylation-related long non-coding RNAs (lncRNAs) in GC are very limited in the literature. We aimed to investigate the prognostic potential of m ⁶A-related lncRNAs in predicting prognosis and monitoring immunotherapy efficacy in GC patients.

Methods

Transcriptome and clinical data were obtained from GC biopsies from Cancer Genome Atlas (TCGA). M ⁶A-related lncRNAs associated with GC were identified by constructing a co-expression network, and the gene pairs differentially expressed in GC were selected using univariate analysis. We constructed a risk model based on prognosis-related lncRNA pairs selected using the LASSO algorithm and quantified the best cutoff by comparing the area under the curve (AUC) for risk stratification. A risk model with the optimal discrimination between high- and low-risk GC patients was established. Its feasibility for overall survival prediction and discrimination of clinicopathological features, tumor-infiltrating immune cells, and biomarkers of immune checkpoint inhibitors between high- and low-risk groups were assessed.

Results

Finally, we identified 11 m ⁶A-related lncRNA pairs associated with GC prognosis based on transcriptome analysis of 375 GC specimens and 32 normal tissues. A risk model was constructed with an AUC of 0.8790. We stratified GC patients into high- and low-risk groups at a cutoff of 1.442. As expected, patients in the low-risk group had longer overall survival versus the high-risk group. Infiltration of cancer-associated fibroblasts, endothelial cells, macrophages, particularly M2 macrophages, and monocytes was more severe in high-risk patients than low-risk individuals, who exhibited high CD4 ⁺ Th1 cell infiltration in GC. Altered expressions of immune-related genes were observed in both groups. PD-1 and LAG3 expressions were found higher in low-risk patients than high-risk patients. Immunotherapy, either single or combined use of PD-1 or CTLA4 inhibitors, had better efficacy in low-risk patients than high-risk patients.

Conclusion

The new risk model based on a 11-m ⁶A-related lncRNA signature can serve as an independent predictor for GC prognosis prediction and may aid in the development of personalized immunotherapy strategies for patients.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12885-021-09062-2.