An integrated multiomics-based risk model for predicting the prognosis and immune microenvironment status in patients...

Papillary thyroid carcinoma (PTC) is the most common type of primary endocrine malignancy. The tumor immune microenvironment (TIME) and genetic alterations play crucial roles in the progression of PTC. With the advance in research, there has been a heightened focus on re-evaluating molecular targeted therapies and identifying novel targets through molecular biology-based approaches. This study aimed to identify robust prognostic biomarkers and to construct a reliable risk model for patients with PTC by integrating multiomics data.

RNA-sequencing (RNA-seq) data from six Gene Expression Omnibus (GEO) datasets and genome-wide association study (GWAS) data were integrated to identify differentially expressed genes (DEGs) and facilitate Mendelian randomization (MR) analysis for causal inference. The CIBERSORT algorithm was employed to evaluate immune cell infiltration. A prognostic risk model was constructed via least absolute shrinkage and selection operator (LASSO) Cox regression and validated in The Cancer Genome Atlas (TCGA) and GEO cohorts. Functional experiments, including Cell Counting Kit-8 (CCK-8), transwell, and wound-healing assays, were conducted to investigate the role of the key gene ALOX15B in PTC cells.

We identified seven PTC-associated genes (ALOX15B, TIAM1, TMC6, GPX3, RAP1GAP, JUN, and PAPSS2) through expression quantitative trait loci and MR analysis. A robust three-gene risk model (ALOX15B, RAP1GAP, and JUN) was established. Patients in the high-risk group exhibited significantly poorer progression-free survival (PFS), which was confirmed to be an independent prognostic factor by multivariate analysis [hazard ratio =1.355, 95% confidence interval (CI): 1.052-1.746; P=0.02]. The high-risk group was characterized by an immunosuppressive TIME-including decreased CD8⁺ T-cell and increased regulatory T-cell abundance-higher tumor mutational burden, and a higher frequency of BRAF mutations. Conversely, the low-risk group showed a higher prevalence of NRAS mutations. In addition, functional assays in vitro revealed that ALOX15B markedly enhanced the proliferative, migratory, and invasive capacities of PTC cells.

A novel three-gene signature was developed and was demonstrated to be an independent prognostic indicator for patients with PTC. This model effectively reflects the intrinsic characteristics of the TIME and genomic instability and can inform risk stratification and therapeutic targeting. Due to its oncogenic activity, ALOX15B may represent a viable therapeutic target in PTC.