Abstract
Background: Genomic instability of N6-methyladenosine (m6A)–related long noncoding RNAs (lncRNAs) plays a pivotal role in the tumorigenesis of lung adenocarcinoma (LUAD). Our study identified a signature of genomic instability of m6A-associated lncRNA signature and revealed its prognostic role in LUAD. Methods: We downloaded RNA-sequencing data and somatic mutation data for LUAD from The Cancer Genome Atlas (TCGA) and the GSE102287 dataset from the Gene Expression Omnibus (GEO) database. The “Limma” R package was used to identify a network of regulatory m6A-related lncRNAs. We used the Wilcoxon test method to identify genomic-instability–derived m6A-related lncRNAs. A competing endogenous RNA (ceRNA) network was constructed to identify the mechanism of the genomic instability of m6A-related lncRNAs. Univariate and multivariate Cox regression analyses were performed to construct a prognostic model for internal testing and validation of the prognostic m6A-related lncRNAs using the GEO dataset. Performance analysis was conducted to compare our prognostic model with the previously published lncRNA models. The CIBERSORT algorithm was used to explore the relationship of m6A-related lncRNAs and the immune microenvironment. Prognostic m6A-related lncRNAs in prognosis, the tumor microenvironment, stemness scores, and anticancer drug sensitivity were analyzed to explore the role of prognostic m6A-related lncRNAs in LUAD. Results: A total of 42 genomic instability–derived m6A-related lncRNAs were differentially expressed between the GS (genomic stable) and GU (genomic unstable) groups of LUAD patients. Four differentially expressed lncRNAs, 17 differentially expressed microRNAs, and 75 differentially expressed mRNAs were involved in the genomic-instability–derived m6A-related lncRNA-mediated ceRNA network. A prediction model based on 17 prognostic m6A-associated lncRNAs was constructed based on three TCGA datasets (all, training, and testing) and validated in the GSE102287 dataset. Performance comparison analysis showed that our prediction model (area under the curve [AUC] = 0.746) could better predict the survival of LUAD patients than the previously published lncRNA models (AUC = 0.577, AUC = 0.681). Prognostic m6A-related-lncRNAs have pivotal roles in the tumor microenvironment, stemness scores, and anticancer drug sensitivity of LUAD. Conclusion: A signature of genomic instability of m6A-associated lncRNAs to predict the survival of LUAD patients was validated. The prognostic, immune microenvironment and anticancer drug sensitivity analysis shed new light on the potential novel therapeutic targets in LUAD.
Highlights
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths globally (Torre et al, 2015; Bray et al, 2018)
42 genome instability–derived m6A-related long noncoding RNA (lncRNA) were differentially expressed between the GS and GU groups based on |logFC|≥1 and false discovery rate adjusted p-value < 0.05
We identified a signature of 17 prognostic m6A-related lncRNAs based on all lung adenocarcinoma (LUAD) patients, a training group, and a testing group for predicting the outcomes of LUAD
Summary
Lung cancer is the most frequently diagnosed cancer and the leading cause of cancer-related deaths globally (Torre et al, 2015; Bray et al, 2018). Recent studies have demonstrated that the characteristics of genomic instability in cancers are associated with clinical implications and prognosis (Sheffer et al, 2009; Sahin et al, 2016). A study demonstrated that EZH2 mediates ribosomal DNA stability via silencing of lncRNA PHACTR2-AS1, which promotes breast cancer cell proliferation and metastasis (Chu et al, 2020). N6-methylandenosine (m6A)–related lncRNAs play a significant role in multiple cancers (Zhang et al, 2019a; Ni et al, 2019; Wang et al, 2019), and an m6A-related lncRNA was developed to predict the diagnosis and prognosis of cancers (Tu et al, 2020). A study developed mutator-derived lncRNA signatures of genome instability for predicting clinical outcomes in breast cancer (Bao et al, 2020). Genomic instability of N6-methyladenosine (m6A)–related long noncoding RNAs (lncRNAs) plays a pivotal role in the tumorigenesis of lung adenocarcinoma (LUAD). Our study identified a signature of genomic instability of m6A-associated lncRNA signature and revealed its prognostic role in LUAD
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