Construction of the prognostic signature of alternative splicing revealed the prognostic predictor and immune microenvironment in head and neck squamous cell carcinoma.

Abstract

Background: Head and neck squamous cell carcinoma (HNSC) is a prevalent and heterogeneous malignancy with poor prognosis and high mortality rates. There is significant evidence of alternative splicing (AS) contributing to tumor development, suggesting its potential in predicting prognosis and therapeutic efficacy. This study aims to establish an AS-based prognostic signature in HNSC patients. Methods: The expression profiles and clinical information of 486 HNSC patients were downloaded from the TCGA database, and the AS data were downloaded from the TCGA SpliceSeq database. The survival-associated AS events were identified by conducting a Cox regression analysis and utilized to develop a prognostic signature by fitting into a LASSO-regularized Cox regression model. Survival analysis, univariate and multivariate Cox regression analysis, and receiver operating characteristic (ROC) curve analysis were performed to evaluate the signature and an independent cohort was used for validation. The immune cell function and infiltration were analyzed by CIBERSORT and the ssGSEA algorithm. Results: Univariate Cox regression analysis identified 2726 survival-associated AS events from 1714 genes. The correlation network reported DDX39B, PRPF39, and ARGLU1 as key splicing factors (SF) regulating these AS events. Eight survival-associated AS events were selected and validated by LASSO regression to develop a prognostic signature. It was confirmed that this signature could predict HNSC outcomes independent of other variables via multivariate Cox regression analysis. The risk score AUC was more than 0.75 for 3years, highlighting the signature's prediction capability. Immune infiltration analysis reported different immune cell distributions between the two risk groups. The immune cell content was higher in the high-risk group than in the low-risk group. The correlation analysis revealed a significant correlation between risk score, immune cell subsets, and immune checkpoint expression. Conclusion: The prognostic signature developed from survival-associated AS events could predict the prognosis of HNSC patients and their clinical response to immunotherapy. However, this signature requires further research and validation in larger cohort studies.