N6-methyladenosine-related lncRNAs identified as potential biomarkers for predicting the overall survival of Asian gastric cancer patients

Abstract

Objective Gastric cancer (GC) is one of the most prevalent malignant tumors in Asian countries. Studies have proposed that lncRNAs can be used as diagnostic and prognostic indicators of GC due to the high specificity of lncRNAs expression involvement in GC. Recently, N6-methyladenosine (m6A) has also emerged as an important modulator of the expression of lncRNAs in GC. This study aimed at establishing a novel m6A-related lncRNAs prognostic signature that can be used to construct accurate models for predicting the prognosis of GC in the Asian population. Methods First, the levels of m6A modification and m6A methyltransferases expression in GC samples were determined using dot blot and western blot analyses. Next, we evaluated the lncRNAs expression profiles and the corresponding clinical data of 88 Asian GC patients retrieved from The Cancer Genome Atlas (TCGA) database. Differential expression of m6A-related lncRNAs between GC and normal tissues was investigated. The relationship between these target lncRNAs and potential immunotherapeutic signatures was also analyzed. Gene set enrichment analysis (GSEA) was performed to identify the malignancy-associated pathways. Univariate Cox regression, LASSO regression, and multivariate Cox regression analyses were performed to establish a novel prognostic m6A-related lncRNAs prognostic signature. Moreover, we constructed a predictive nomogram and determined the expression levels of nine m6A-related lncRNAs in 12 pairs of clinical samples. Results We found that m6A methylation levels were significantly increased in GC tumor samples compared to adjacent normal tissues, and the increase was positively correlated with tumor stage. Patients were then divided into two clusters (cluster 1 and cluster 2) based on the differential expression of the m6A-related lncRNAs. Results showed that there was a significant difference in survival probability between the two clusters (p = 0.018). Notably, the low survival rate in cluster 2 may be associated with high expression of immune cells (resting memory CD4+ T cells, p = 0.027; regulatory T cells, p = 0.0018; monocytes, p = 0.00095; and resting dendritic cells, p = 0.015), and low expression of immune cells (resting NK cells, p = 0.033; and macrophages M1, p = 0.045). Enrichment analysis indicated that malignancy-associated biological processes were more common in the cluster 2 subgroup. Finally, the risk model comprising of six m6A-related lncRNAs was identified as an independent predictor of prognoses, which could divide patients into high- or low-risk groups. Time-dependent ROC analysis suggested that the risk score could accurately predict the prognosis of GC patients. Patients in the high-risk group had worse outcomes compared to patients in the low-risk group, and the risk score showed a positive correlation with immune cells (resting memory CD4+ T cells, R = 0.31, P = 0.038; regulatory T cells, R = 0.42, P = 0.0042; monocytes, R = 0.42, P = 0.0043). However, M1 macrophages (R = -0.37, P = 0.012) and resting NK cells (R = -0.31, P = 0.043) had a negative correlation with risk scores. Furthermore, analysis of clinical samples validated the weak positive correlation between the risk score and tumor stage. Conclusions The risk model described here, based on the six m6A-related lncRNAs signature, and may predict the clinical prognoses and immunotherapeutic response in Asian GC patients.

A methylation- and immune-related lncRNA signature to predict ovarian cancer outcome and uncover mechanisms of chemoresistance

“…The methylation-related genes are 50 recognized methylation regulators extracted from previous studies including “writers”, “erasers”, and “readers” [ 28 , 35 – 37 ]. We obtained the profiles of methylation-related genes from the TCGA database.…”

The emerging role of m6A modification of non-coding RNA in gastrointestinal cancers: a comprehensive review

“…The identification of m 6 A-associated protein-coding genes in pan-cancer analyses has provided novel candidate targets for clinical diagnosis and treatment ( Shen et al, 2021 ). Recent evidence suggests that m 6 A-associated ncRNAs could be used to construct prediction models for prognosis in GI cancer ( Wang et al, 2022b ; Xu et al, 2022 ). Due to dynamic and reversible changes in m 6 A regulators during cancer development, m 6 A methylation could serve as a prognostic biomarker to guide therapeutic schemes for numerous cancer types ( Ji G et al, 2020 ; Jin et al, 2021 ).…”

Construction and validation of a novel prognostic model using the cellular senescence-associated long non-coding RNA in gastric cancer: a biological analysis

“…But the prognosis and survival of GC are not good. Therefore, some new prognostic models have emerged to help clinical judgment and guide clinical treatment [e.g., N6-methyladenosinerelated lncRNAs (12), ferroptosis-related lncRNAs (13), and hypoxia-related lncRNAs (14), etc.]. However, there is no research on cellular senescence-related lncRNAs in the stomach adenocarcinoma (STAD) prognostic model.…”