Identification of a m6A-related ferroptosis signature as a potential predictive biomarker for lung adenocarcinoma

Abstract

Background: Both N6-methyladenosine (m⁶A) and ferroptosis-related genes are associated with the prognosis of lung adenocarcinoma. However, the predictive value of m⁶A-related ferroptosis genes remains unclear. Here, we aimed to identify the prognostic value of m⁶A-related ferroptosis genes in lung adenocarcinoma.

Methods: Lung adenocarcinoma sample data were downloaded from the University of California Santa Cruz Xena and Gene Expression Omnibus databases. Spearman's correlation analysis was used to screen for m⁶A-related ferroptosis genes. Univariate Cox regression, Kaplan-Meier, and Lasso analyses were conducted to identify prognostic m⁶A-related ferroptosis genes, and stepwise regression was used to construct a prognostic gene signature. The predictive value of the gene signature was assessed using a multivariate Cox analysis. In the validation cohort, survival analysis was performed to verify gene signature stability. The training cohort was divided into high- and low-risk groups according to the median risk score to assess differences between the two groups in terms of gene set variation analysis, somatic mutations, and tumor immune infiltration cells.

Results: Six m⁶A-related ferroptosis genes were used to construct a gene signature in the training cohort and a multivariate Cox analysis was conducted to determine the independent prognostic value of these genes in lung adenocarcinoma. In the validation cohort, Kaplan-Meier and receiver operating characteristic analyses confirmed the strong predictive power of this signature for the prognosis of lung adenocarcinoma. Gene set variation analysis showed that the low-risk group was mainly related to immunity, and the high-risk group was mainly related to DNA replication. Somatic mutation analysis revealed that the TP53 gene had the highest mutation rate in the high-risk group. Tumor immune infiltration cell analysis showed that the low-risk group had higher levels of resting CD4 memory T cells and lower levels of M0 macrophages.

Conclusion: Our study identified a novel m⁶A-related ferroptosis-associated six-gene signature (comprising SLC2A1, HERPUD1, EIF2S1, ACSL3, NCOA4, and CISD1) for predicting lung adenocarcinoma prognosis, yielding a useful prognostic biomarker and potential therapeutic target.

Keywords: Bioinformatics; Ferroptosis; Lung adenocarcinoma; Prognosis; m6A.