Establishment of a ferroptosis-related gene signature for prognosis in lung adenocarcinoma patients.

Jingjing Cai,Hongsheng Li,Yongchun Zhou,Chunyan Li,Xiaoxiong Wang

doi:10.7717/peerj.11931

Abstract

ObjectiveLung cancer is the most common malignancy worldwide and exhibits both high morbidity and mortality. In recent years, scientists have made substantial breakthroughs in the early diagnosis and treatment of lung adenocarcinoma (LUAD), however, patient prognosis still shows vast individual differences. In this study, bioinformatics methods were used to identify and analyze ferroptosis-related genes to establish an effective signature for predicting prognosis in LUAD patients.MethodsThe gene expression profiles of LUAD patients with complete clinical and follow-up information were downloaded from two public databases, univariate Cox regression and multivariate Cox regression analysis were used to obtain ferroptosis-related genes for constructing the prognos tic risk model, AUC and calibration plot were used to evaluate the predictive accuracy of the FRGS and nomogram.ResultsA total of 74 ferroptosis-related differentially expressed genes (DEGs) were identi fied between LUAD and normal tissues from The Cancer Genome Atlas (TCGA) database. A five-gene panel for prediction of LUAD prognosis was established by multivariate regression and was verified using the GSE68465 cohort from the Gene Expression Omnibus (GEO) database. Patients were divided into two different risk groups according to the median risk score of the five genes. Based on Kaplan-Meier (KM) analysi, the OS rate of the high-risk group was markedly worse than that of the low-risk group. We also found that risk score was an independent prognostic indicator. The receiver operating characteristic ROC curve showed that the proposed model had good prediction ability. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) functional analyses indicated that risk score was prominently enriched in ferroptosis processes. Moreover, at the score of immune-associated gene sets, significant differences were found between the two risk groups.ConclusionsThis study demonstrated that ferroptosis-related gene signatures can be used as a potential predictor for the prognosis of LUAD, thus providing a novel strategy for individualized treatment in LUAD patients.

Highlights

The incidence and mortality of lung cancer rank first in the world (Siegel, Miller & Jemal, 2020)
Scientists have recently discovered a novel type of programmed cell death that differs from apoptosis and cell necrosis, called ferroptosis, which depends on iron ions and reactive oxygen species (ROS) to induce lipid peroxide accumulation (Latunde-Dada, 2017; Stockwell et al, 2017; Conrad et al, 2018)
We searched the lung adenocarcinoma (LUAD) gene expression dataset from the Gene Expression Omnibus (GEO; http://www.ncbi.nlm.nih.gov/geo/) database and collected a cohort based on the GPL96 platform, resulting in 441 cancer patients with complete clinical information

Summary

Introduction

The incidence and mortality of lung cancer rank first in the world (Siegel, Miller & Jemal, 2020). LUAD treatments include surgery, radiotherapy, and chemotherapy, as well as targeted therapy and immunotherapy (Eberhardt & Stuschke, 2015). An increasing body of evidence suggests that ferroptosis is involved in the initiation, progression, and suppression of cancer (Fearnhead, Vandenabeele & Vanden Berghe, 2017). Induction of ferroptosis may be an emerging target for the treatment of malignant tumors (Liang et al, 2019; Hassannia, Vandenabeele & Vanden Berghe, 2019), and polyunsaturated fatty acid (PUFA) in phospholipids, redox active iron, and lipid peroxidation (LPO) repair defects, may determine the susceptibility of cancer cells to ferroptosis. P53 is the most closely related tumor suppressor gene. It cannot only induce apoptosis, and induce ferroptosis. P53 can inhibit the absorption of cystine by systemxc by inhibiting the transcription of SLC7A11 (Wang et al, 2016), resulting in the inhibition of the GSH / GPx4 pathway, the reduction of cell antioxidant capacity and the occurrence of ferroptosis. Jiang et al (2015) confirmed that SLC7A11 is a new regulatory target of p53 gene

Methods

Results

Discussion

Conclusion