Abstract
Squamous cell carcinoma of the head and neck (HNSCC) is one of the six most common malignancies. HNSCC has both a high incidence and poor prognosis, and its prognostic factors remain unclear. Ferroptosis is a newly discovered form of programmed cell death that is iron-dependent. Increasing evidence indicates that targeting ferroptosis may present a new form of anti-tumor treatment. However, the prognostic value of ferroptosis-related genes (FRGs) in HNSCC is unclear. This study was designed to identify molecular markers associated with ferroptosis that influence prognosis in patients with HNSCC. We used HNSCC tumor and normal data from The Cancer Genome Atlas (TCGA) to identify prognosis-related FRGs. An FRG-based prognostic risk score was constructed, and its prognostic value for patients with HNSCC was evaluated using receiver operating characteristic curve (ROC) and nomogram analyses. The model was validated using the Gene Expression Omnibus (GEO) database. Univariate Cox regression analysis in patients with HNSCC revealed 11 FRGs that were significantly associated with overall survival (OS). We constructed a ferroptosis risk score model based on five genes and divided the patients into different risk groups based on its median value. Kaplan-Meier curve analysis showed that patients with a higher ferroptosis risk score had shorter OS (TCGA training set: P < 0.001, TCGA validation set: P < 0.05,GEO validation set: P < 0.001), and Gene Expression Profiling Interactive Analysis (GEPIA) further verified the relationships between these five genes and prognosis in patients with HNSCC. Multivariate Cox regression analysis showed that the risk score remained an independent predictor of OS after the exclusion of clinical confounders (HR > 1, P < 0.01). Significant differences in gene function enrichment analysis and immune cell infiltration status were identified between the two groups. The prognostic model can be used to predict the prognosis of patients with HNSCC. Moreover, the five FRGs may affect ferroptosis in HNSCC and thereby represent potential treatment targets. These results provide new directions for HNSCC treatment.
Highlights
Squamous cell carcinoma is a common malignant tumor of the head and neck (HNSCC)
Cox regression analyses were used to construct a ferroptosis-related prognosis model consisting of five genes (SLC7A11, AURKA, TRIB3, AKR1C3, and CAV1), and internal and external validation was conducted
gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) enrichment analyses of genes that were differentially expressed in the different risk groups showed significant enrichment in oxidative stress-related pathways associated with ferroptosis, as well as in immune-related pathways
Summary
Squamous cell carcinoma is a common malignant tumor of the head and neck (HNSCC). The incidence of HNSCC is trending upwards, with approximately 600,000 new cases diagnosed yearly (Torre et al, 2015; Shield et al, 2017; Solomon et al, 2018). Clinical studies have shown that adjuvant therapy for advanced HNSCC using platinumbased chemotherapy is effective and can significantly improve patient survival rates. The complex mutation landscape of HNSCC may be the main reason for the low response rate of targeted therapy, as most tumors are caused by multiple genetic drivers that have evolved further after multiple rounds of chemoradiotherapy. This highlights the importance of targeted therapy selection for tumors. We analyzed The Cancer Genome Atlas (TCGA) database transcriptome data of 506 tumors to comprehensively describe differences in FRG transcription levels in HNSCC, and to provide a theoretical basis for ferroptosis-targeting HNSCC treatments. Understanding the level of ferroptosis in HNSCC may help to develop a theoretical basis for ongoing basic research in ferroptosis oncology, accelerate the development of therapeutic ferroptosis targets in HNSCC, and guide clinical research
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