Gene Characteristics and Prognostic Values of m⁶A RNA Methylation Regulators in Nonsmall Cell Lung Cancer

N⁶-methyladenosine (m⁶A) is the most common internal modification present in mRNAs and long noncoding RNAs (lncRNAs), associated with tumorigenesis and cancer progression. However, little is known about the roles of m⁶A and its regulatory genes in nonsmall cell lung cancer (NSCLC). Here, we systematically explored the roles and prognostic significance of m⁶A-associated regulatory genes in NSCLC.

The copy number variation (CNV), mutation, mRNA expression data, and corresponding clinical pathology information of 1057 NSCLC patients were downloaded from the cancer genome atlas (TCGA) database. The gain and loss levels of CNVs were determined by utilizing segmentation analysis and GISTIC algorithm. The GSEA was conducted to explore the functions related to different levels of m⁶A regulatory genes. Logrank test was utilized to assess the prognostic significance of m⁶A-related gene's CNV.

The genetic alterations of ten m⁶A-associated regulators were identified in 102 independent NSCLC samples and significantly related to advanced tumor stage. Deletions or shallow deletions corresponded to lower mRNA expression while copy number gains or amplifications were related to increased mRNA expression of m⁶A regulatory genes. Survival analysis showed the patients with copy number loss of FTO with worse disease-free survival (DFS) or overall survival (OS). Besides, copy number loss of YTHDC2 was also with poor OS for NSCLC patients. Moreover, high FTO expression was significantly associated with oxidative phosphorylation, translation, and metabolism of mRNA.

Our findings provide novel insight for better understanding of the roles of m⁶A regulators and RNA epigenetic modification in the pathogenesis of NSCLC.