Comprehensive Analysis of Ferroptosis Regulators in Lung Adenocarcinomas Identifies Prognostic and Immunotherapy-Related Biomarkers

Abstract

Ferroptosis is a newly discovered type of programmed cell death that differs from canonical apoptosis. However, the potential role of ferroptosis in lung adenocarcinoma (LUAD) has not been elaborated. In total, 1,328 samples from databases and 36 ferroptosis regulators were included in this study. By combining random survival forest and principal component analysis algorithms, a robust prognostic ferroptosis-related risk score (FRRS) was constructed, and the performance was validated in three independent datasets. Based on the median risk score, two subgroups were identified. Then, comparisons, including of mutational profiles, functional enrichment analyses and immune components, were conducted between subgroups. An immunotherapy cohort was applied to explore potential therapeutic-related biomarkers. Finally, the clinical utility of FRRS was validated in a proteomic cohort. In the TCGA-LUAD cohort, FRRS was calculated using the expression of 11 selected genes, and patients with high FRRS had a significantly (p < 0.001) worse prognosis than those with low FRRS. Multivariate regression suggested that FRRS was an independent prognostic factor. Functional enrichment analysis indicated that FRRS was mainly involved in cell cycle, metabolic and immune-related pathways. Furthermore, FRRS was shown to be significantly (p < 0.001) associated with the abundance of CD8 T cells and tumor mutation burden (TMB). The combination of TMB and FANCD2 expression, the main contributor to FRRS, substantially increased the precision of predicting the therapeutic response. In conclusion, the present study revealed the potential role of ferroptosis regulators in LUAD and identified ferroptosis-related biomarkers for prognostic and immunotherapeutic predictions.

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

“…Before us, FRG signatures had been established and applied for LUAD in recent research ( Gao et al, 2021 ; Sun et al, 2021 ). Even so, our signature has better robustness with better predictive ability, providing more solid clinical reference.…”

Ferroptosis in Lung Cancer: From Molecular Mechanisms to Prognostic and Therapeutic Opportunities

“…Up to now, thanks to The Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) datasets, a significant number of studies have been conducted to analyze the expression profile of genes involved in ferroptosis in patients with lung cancer, particularly LUAD (81)(82)(83)(84)(85)(86)(87)(88)(89)(90)(91)(92)(93). As seen in Table 1, these studies have shown that ferroptosis regulator genes can predict the prognosis and overall survival of patients very efficiently.…”

Ferroptosis-Related lncRNA Signature Predicts Prognosis and Immunotherapy Efficacy in Cutaneous Melanoma

“…Ferroptosis affects cell proliferation, metastasis, and immune response in cancers. Because ferroptosisrelated genes have important regulatory roles in cancer progression, they have been used to construct risk scores to predict the prognosis of many cancers, including hepatocellular carcinoma [26][27][28] , glioma [29][30][31] , lung adenocarcinoma [32][33][34] , breast cancer [35][36][37] , pancreatic cancer 38,39 , ovarian cancer 40,41 , esophageal cancer 42,43 , colon cancer 44,45 , cervical cancer 46 , clear-cell renal cell carcinoma 47 , soft tissue sarcoma 48 , thyroid cancer 49 , and gastric cancer 50 . However, existing ferroptosis-related gene signatures have a poor predictive ability for the prognosis of CM patients in the most recent studies (Ni Zeng et al, 2021, Congcong Xu et al, 2021.…”