Papillary thyroid carcinoma (PTC), though genetically characterized, lacks comprehensive epigenomic profiling. Here we present the first combined analysis of 5-methylcytosine (5mC), 5-hydroxymethylcytosine (5hmC), and 6-methyladenine (6mA) in PTC pathogenesis. Using mDIP-seq on matched tumor and adjacent normal tissues from six treatment-naïve patients, we mapped genome-wide distributions of these modifications, revealing distinct spatial patterns and tumor-specific differentially methylated regions (DMRs) with modification-specific functional partitioning. Silhouette-guided feature selection refined 7,117 DMRs to a 187-locus diagnostic panel achieving robust tumor-normal discrimination, with chromosomes 16 and 19 as recurrent epigenetic hotspots (2.1-7.9-fold enrichment). Integration of TCGA data revealed mutation-dependent epigenetic-transcriptional associations: BRAF-mutant tumors showed selective upregulation of epigenetically dysregulated genes, whereas RAS-mutant tumors displayed distinct transcriptional patterns. Co-expression network analysis highlighted disrupted transcriptional coordination in tumors. This work establishes a multidimensional epigenetic framework for PTC with combinatorial diagnostic signatures and condition-specific associations between DNA modifications and driver mutations (BRAF vs. RAS).
Li et al. (Wed,) studied this question.
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