Molecular identification of an immunity- and Ferroptosis-related gene signature in non-small cell lung Cancer

Taisheng Liu,Jian Zhang,Xiaoshan Hu,Honglian Luo,Jinye Zhang

doi:10.1186/s12885-021-08541-w

Abstract

BackgroundLung cancer is one of the dominant causes of cancer-related deaths worldwide. Ferroptosis, an iron-dependent form of programmed cell death, plays a key role in cancer immunotherapy. However, the role of immunity- and ferroptosis-related gene signatures in non-small cell lung cancer (NSCLC) remain unclear.MethodsRNA-seq data and clinical information pertaining to NSCLC were collected from The Cancer Genome Atlas dataset. Univariate and multivariate Cox regression analyses were performed to identify ferroptosis-related genes. A receiver operating characteristic (ROC) model was established for sensitivity and specificity evaluation. Gene ontology enrichment and Kyoto Encyclopedia of Genes and Genomes pathway analyses were performed to explore the function roles of differentially expressed genes.ResultsA signature composed of five ferroptosis-related genes was established to stratify patients into high- and low-risk subgroups. In comparison with patients in the low-risk group, those in the high-risk one showed significantly poor overall survival in the training and validation cohorts (P < 0.05). Multivariate Cox regression analysis indicated risk score to be an independent predictor of overall survival (P < 0.01). Further, the 1-, 2-, and 3-year ROCs were 0.623 vs. 0.792 vs. 0.635, 0.644 vs. 0.792 vs. 0.634, and 0.631 vs. 0.641 vs. 0.666 in one training and two validation cohorts, respectively. Functional analysis revealed that immune-related pathways were enriched and associated with abnormal activation of immune cells.ConclusionsWe identified five immunity- and ferroptosis-related genes that may be involved in NSCLC progression and prognosis. Targeting ferroptosis-related genes seems to be an alternative to clinical therapy for NSCLC.

Highlights

Lung cancer is one of the dominant causes of cancer-related deaths worldwide
Ferroptotic cancer cells produce a plethora of oxidized lipid mediators to affect anti-tumor immunity, and a small proportion of cells undergoing ferroptosis are capable of suppressing the immune system, enhancing tumor growth [15]
Interaction network analysis showed that SLC7A11, GCLC, HMOX1, GCLM, G6PD, NQO1, and NOX1 were the significant hub genes (Fig. 2d-e), suggesting that they are mainly responsible for regulating ferroptosis in non-small cell lung cancer (NSCLC)

Summary

Introduction

Lung cancer is one of the dominant causes of cancer-related deaths worldwide. Ferroptosis, an irondependent form of programmed cell death, plays a key role in cancer immunotherapy. The role of immunity- and ferroptosis-related gene signatures in non-small cell lung cancer (NSCLC) remain unclear. Despite extensive research on molecular targeted therapies and checkpoint inhibitors, > 50% patients die within 1 year of NSCLC diagnosis, and the 5-year overall survival (OS) rate is < 18% [3]. These data indicate that there is an urgent need for novel therapeutic research and comprehensive analyses to elucidate the molecular mechanisms underlying NSCLC, which should facilitate the identification of new therapeutic targets. The relationship between NSCLC patient prognosis and immunity- and ferroptosis-related genes remains unknown, making the development of ferroptosis therapy for NSCLC a major challenge

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Conclusion