Abstract
BackgroundAccumulating studies have demonstrated that lncRNAs play vital roles in the prognosis of gastric cancer (GC); however, the prognostic value of N6-methyladenosine-related lncRNAs has not been fully reported in GC. This study aimed to construct and validate an m6A-related lncRNA pair signature (m6A-LPS) for predicting the prognosis of GC patients.MethodsGC cohort primary data were downloaded from The Cancer Genome Atlas. We analysed the coexpression of m6A regulators and lncRNAs to identify m6A-related lncRNAs. Based on cyclical single pairing along with a 0-or-1 matrix and least absolute shrinkage and selection operator-penalized regression analyses, we constructed a novel prognostic signature of m6A-related lncRNA pairs with no dependence upon specific lncRNA expression levels. All patients were divided into high-risk and low-risk group based on the median risk score. The predictive reliability was evaluated in the testing dataset and whole dataset with receiver operating characteristic (ROC) curve analysis. Gene set enrichment analysis was used to identify potential pathways.ResultsFourteen m6A-related lncRNA pairs consisting of 25 unique lncRNAs were used to construct the m6A-LPS. Kaplan–Meier analysis showed that the high-risk group had poor prognosis. The area under the curve for 5-year overall survival was 0.906, 0.827, and 0.882 in the training dataset, testing dataset, and whole dataset, respectively, meaning that the m6A-LPS was highly accurate in predicting GC patient prognosis. The m6A-LPS served as an independent prognostic factor for GC patients after adjusting for other clinical factors (p < 0.05). The m6A-LPS had more accuracy and a higher ROC value than other prognostic models for GC. Functional analysis revealed that high-risk group samples mainly showed enrichment of extracellular matrix receptor interactions and focal adhesion. Moreover, N-cadherin and vimentin, known biomarkers of epithelial–mesenchymal transition, were highly expressed in high-risk group samples. The immune infiltration analysis showed that resting dendritic cells, monocytes, and resting memory CD4 T cells were significantly positively related to the risk score. Thus, m6A-LPS reflected the infiltration of several types of immune cells.ConclusionsThe signature established by pairing m6A-related lncRNAs regardless of expression levels showed high and independent clinical prediction value in GC patients.
Highlights
Gastric cancer (GC) is a major global disease, and it is the fifth most common cancer and the fourth most lethal malignancy
The results showed that the 5-year area under the curve (AUC) value of our prognostic model was 0.882, showing obviously higher predictive value and accuracy than the existing prognostic models Lv.signature (5-year AUC = 0.630), Liu.signature (5-year AUC = 0.675), and Mao. signature (5-year AUC = 0.577)
The results revealed that m6A-related Long non-coding RNAs (lncRNAs) pair signature (m6A-LPS) was an independent factor for predicting the prognosis of gastric cancer (GC) (p < 0.001) (Fig. 5d, e)
Summary
Gastric cancer (GC) is a major global disease, and it is the fifth most common cancer and the fourth most lethal malignancy. Of the over 160 RNA post-transcriptional regulatory marks in multiple RNA species, N6-methyladenosine (m6A) is the most common form modification on mRNA in higher eukaryotes, and it plays a vital role in RNA splicing, export, stability and translation [6]. Signal transducers, including YT521-B homology (YTH) domain family members (YTHDF1, YTHDF2, and YTHDF3), YTH domain-containing proteins (YTHDC1 and YTHDC2), heterogeneous nuclear ribonucleoproteins family members (HNRNP and HNRNPA2B1), and insulin-like growth factor 2 mRNA-binding proteins (IGF2BPs; including IGF2BP1, IGF2BP2, and IGF2BP3), affect the reading of RNA methylation information, translation, stability and degradation of downstream RNAs [4, 13, 14]. Accumulating studies have demonstrated that lncRNAs play vital roles in the prognosis of gastric cancer (GC); the prognostic value of N6-methyladenosine-related lncRNAs has not been fully reported in GC. This study aimed to construct and validate an m6A-related lncRNA pair signature (m6A-LPS) for predicting the prognosis of GC patients
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