Development and clinical validation of a necroptosis-related gene signature for prediction of prognosis and tumor immunity in lung adenocarcinoma

Kai Lei; Binghua Tan; Ruihao Liang; Yingcheng Lyu; Kexi Wang; Wenjian Wang; Kefeng Wang; Xueting Hu; Duoguang Wu; Huayue Lin; Minghui Wang

Development and clinical validation of a necroptosis-related gene signature for prediction of prognosis and tumor immunity in lung adenocarcinoma

Am J Cancer Res. 2022 Nov 15;12(11):5160-5182. eCollection 2022.

Authors

Kai Lei^{1

2}, Binghua Tan^{1

2}, Ruihao Liang^{1

2}, Yingcheng Lyu^{1

2}, Kexi Wang^{1

2}, Wenjian Wang^{1

2}, Kefeng Wang^{1

2}, Xueting Hu^{1

2}, Duoguang Wu^{1

2}, Huayue Lin^{1

3}, Minghui Wang^{1

2}

Affiliations

¹ Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-sen Memorial Hospital, Sun Yat-sen University Guangzhou, Guangdong, China.
² Department of Thoracic Surgery, Sun Yat-sen Memorial Hospital, Sun Yat-sen University Guangzhou, Guangdong, China.
³ Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University Guangzhou, Guangdong, China.

PMID: 36504901
PMCID: PMC9729905

Abstract

Necroptosis is a new programmed formation of necrotizing cell death, which plays important role in tumor biological regulation, including tumorigenesis and immunity. In this study, we aimed to establish and validate a prediction model based on necroptosis-related genes (NRGs) for lung adenocarcinoma (LUAD) prognosis and tumor immunity. The training set consisted of samples from The Cancer Genome Atlas (TCGA) dataset (n = 334), and the validation sets consisted of samples from the Gene Expression Omnibus (GEO) (n = 439) and clinical (n = 20) datasets. Gene Oncology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that 28 necroptosis-related differentially expressed genes (DEGs) were enriched in cell death and immune regulation. RT-qPCR and western blot results showed the low expression of necroptosis markers in LUAD cells. A prognostic gene signature based on 6 NRGs (PYGB, IL1A, IFNAR2, BIRC3, H2AFY2, and H2AFX) was constructed and the risk score was calculated. Multivariate Cox regression analysis showed that the risk score was an independent risk factor [hazard ratio (HR) = 1.220, 95% confidence interval (CI): 1.154-1.290, P<0.001]. In the TCGA cohort, a high-risk score was associated with poor prognosis, weak immune infiltration, and low expression at immune checkpoints, which was validated in the GEO and clinical cohorts. Our findings showed that the patients in the low-risk group had a better progression-free survival (PFS) [not reached vs. 8.5 months, HR = 0.18, 95% CI: 0.04-0.72, P<0.001] than those in the high-risk score group. Immunotherapy tolerance was found to be correlated with the high-risk score, and the risk score combined with PD-L1 (AUC = 0.808, 95% CI: 0.613-1.000) could better predict the immunotherapy response of LUAD. A nomogram was shown to have a strong ability to predict the individual survival rate of patients with LUAD in the TCGA and GSE68465 cohorts. We constructed and validated a potential prognostic signature consisting of 6 NRGs to predict the prognosis and tumor immunity of LUAD, which may be helpful to guide the individualized immunotherapy of LUAD.

Keywords: Necroptosis; immunotherapy; lung adenocarcinoma; prognosis; tumor microenvironment.