The prognostic value and multiomic features of m6A-related risk signature in lung adenocarcinoma.

OBJECTIVES: N6-methyladenosine (m6A), a predominant RNA modification, has been recently linked to messenger RNA splicing, stability and expression, and its dysregulation may be important in the initiation as well as development of human cancers. The current study was proposed to investigate the clinico-pathological value and multiomic characteristics of m6A-linked genes in the diagnosis and prognosis of lung adenocarcinoma (LUAD). METHODS: The expression levels and mutation types of 21 previously identified m6A regulators were analyzed using the TCGA (The Cancer Genome Atlas) database. The patients were categorized into two groups, a training group (n=392) and a testing group (n=98). Next, the prognostic score of m6A regulators was determined by the Cox survival analysis and a regression model of LASSO to develop a risk profile for patients with LUAD. Moreover, features of risk signature, including chemosensitivity, tumor immune microenvironment and genetic mutation, were also explored. RESULTS: In total, 18 of 21 m6A regulators showed significantly differential expression in LUAD (P<0.05). Among them, 6 genes were observed to be associated with the Overall Survival (OS) of patients with LUAD. Three genes (IGF2BP1 and 2, and HNRNPC) were further evaluated as a prognostic signature in LUAD. Patients, grouped as high risk based on the median of risk score, had poorer OS in comparison with those in low-risk group (P<0.05). The accuracy of our prognostic signatures was high: the AUC were 0.67, 0.59, 0.64 (training set), and 0.65, 0.69, 0.64 (testing set) at survival of 1- , 3- and 5-year, respectively. The prognostic performance of IGF2BP1, IGF2BP2 and HNRNPC was successfully validated in two independent external cohorts. High-risk score was an indicator of chemoresistance, TP53 mutation and increased infiltration of immune cells, and in vitro assessment of the cellular function of HNRNPC confirmed that the gene is involved in cell proliferation and invasion. CONCLUSION: The prognostic signature based on m6A regulators might provide novel insights into prognostic assessment and individualized treatment for patients with LUAD.