Methylation-Driven Gene Signature as a Prognostic Indicator in Papillary Thyroid Carcinoma

Thyroid cancer (TC) is the most common endocrine tumor, and its incidence has risen over the last decade. DNA methylation (DNAm) abnormalities are a feature of malignancies and have been linked to the growth of neoplasms such as papillary thyroid carcinoma (PTC). A comprehensive analysis of DNA methylation and transcriptome data was conducted to identify differentially expressed genes that are prognostically associated with PTC, based on genome-wide DNA methylation patterns. A predictive model for overall survival (OS) was developed using LASSO regression with tenfold cross-validation and Cox regression analysis, with P < 0.05 as the significance threshold. The accuracy and effectiveness of this model were subsequently validated. After analyzing the clinical parameters, a nomogram was constructed and evaluated, with a C-index of 0.939 to assess its predictive performance. Prognostic risk models for six DNAm-driven genes were constructed and validated. The prognostic value of a gene signature consisting of six methylation-related genes in patients with thyroid cancer (THCA) was confirmed through the analysis of Kaplan-Meier survival curves and time-dependent receiver operating characteristic curves. The predictive accuracy of the model was demonstrated by the areas under the curves (AUCs) for the 1-, 3-, and 5-year OS predictions, which were 0.769, 0.795, and 0.762, respectively, in the training dataset. In the testing dataset, the AUCs for these time points were 0.906, 0.816, and 0.900, respectively. Furthermore, univariate and multivariate regression analyses revealed that prognostic model risk scores may be employed as independent prognostic factors for THCA patients. Moreover, pathway enrichment analyses suggest that these DNAm-driven genes may influence tumor progression by affecting signaling pathways such as the "Type II diabetes mellitus", and "TGF-beta signaling pathways". The altered status of the DNAm-driven genes (FHL2, THRSP, PRDM1, NPC2, MREG, and DPP4) was significantly associated with OS in PTC patients.