Clinical Implication of N6-Methylandenosine-Related lncRNAs in Non-Small Cell Lung Cancer

Abstract Background: Non-small-cell lung cancer (NSCLC) represents the leading cause of cancer-related deaths worldwide and is highly heterogeneous. The N6-methyladenosine (m6A) RNA, a vital contributor to the outcomes of cancer, can modify long non-coding RNAs (lncRNAs), thereby influencing the transcript stability, gene expression, and serving a wide array of biological functions. However, the role of m6A-related lncRNAs in NSCLC remains largely unknown. Methods: We identified a group of m6A-related lncRNAs (m6ARLncRNAs) by using co-expression analysis in 1835 NSCLC patients from The Cancer Genome Atlas (TCGA) (N=1145) and Gene Expression Omnibus (GEO) (N=690) datasets. We employed consensus unsupervised clustering analysis to explore molecular patterns based on the expression of m6ARLncRNAs. Then we filtered m6ARLncRNAs by Cox regression and LASSO regression to construct a m6ARLncRNAs signature (m6ARLncSig) and further evaluated m6ARLncSig with external and experimental validation by using qRT-PCR. We analyzed the correlation between m6ARLncSig scores groups with clinical features, chemotherapeutic sensitivity and radiotherapeutic response. Finally, we established a nomogram for prognosis prediction in patients with LUAD and validated it in the testing set and the entire TCGA dataset. Results: We constructed a m6ARLncSig for prognosis prediction of patients consisting of 12 m6ARLncRNAs. The m6ARLncSig divided patients into a high-risk group and a low-risk one, which had significantly different OS and could independently predict the prognosis of patients. Meanwhile, we revealed that patients in the high- and low-risk groups differed in tumor-infiltrating immune cells, and chemotherapeutic sensitivity, and biological pathways. Of note, we found that m6ARLncSig was associated with age, tumor stage, and radiotherapeutic response, indicating they were clinically relevant. Conclusions: Our study demonstrated that m6ARLncSig could act as a potential biomarker for evaluating the prognosis and therapeutic efficacy in NSCLC patients.