Ferroptosis-Related Genes in Lung Adenocarcinoma: Prognostic Signature and Immune, Drug Resistance, Mutation Analysis

Abstract

It is reported that ferroptosis has close relation with tumorigenesis and drug resistance. However, the clinical significance of ferroptosis in lung adenocarcinoma (LUAD) remains elusive, and the potential targets for ferroptosis-based treatment are limited. In this study, we constructed a 15-gene prognostic signature predicting overall survival based on ferroptosis-related genes (ferroptosis driver genes <i>VDAC2</i>, <i>GLS2</i>, <i>FLT3</i>, <i>TLR4</i>, <i>PHKG2</i>, phosphogluconate dehydrogenase (<i>PGD</i>), <i>PANX1</i>, <i>KRAS</i>, <i>PEBP1</i>, <i>ALOX15</i>, and <i>ALOX12B</i>, and suppressor genes <i>ACSL3</i>, <i>CISD1</i>, <i>FANCD2</i>, and <i>SLC3A2</i>) in The Cancer Genome Atlas (TCGA)-LUAD cohort. The signature's predictive ability was validated in the GSE68465 and GSE72094 cohorts by survival analysis and independent prognostic analysis with clinical features. Nomograms were provided for clinical reference. Functional analysis revealed that ferroptosis was closely related to cell cycle, cell metabolism, and immune pathways. Pan-cancer analysis comprehensively analyzed these 15 genes in 33 cancer types, indicating that the heterogeneity of 15 genes was evident across different cancer types. Besides, these genes were critical regulators modulating drug resistance, tumor microenvironment infiltration, and cancer stemness. Then, we screened 10 genes (<i>TLR4</i>, <i>PHKG2</i>, <i>PEBP1</i>, <i>GLS2</i>, <i>FLT3</i>, <i>ALOX15</i>, <i>ACSL3</i>, <i>CISD1</i>, <i>FANCD2</i>, and <i>SLC3A2</i>) as potential targets for further research because their biological functions in ferroptosis were consistent with their prognostic significance. Somatic mutation and copy number variation analysis revealed that the alteration rates of <i>KRAS</i>, <i>PGD</i>, and <i>ALOX15</i> were more than 1% and significantly associated with overall survival in LUAD. Moreover, the expression of <i>KRAS</i> and <i>PGD</i> was positively related to tumor mutation burden, indicating that <i>KRAS</i> and <i>PGD</i> could serve as novel biomarkers for predicting immunotherapy response rate. Our study identified and validated a ferroptosis-related gene signature for LUAD, provided a 10-gene set for future research, and screened <i>KRAS</i> and <i>PGD</i> as potential novel immunotherapy biomarkers.