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<p>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: <i>BRAF</i>-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 (<i>BRAF vs. RAS</i>).</p>

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Combined epigenomic landscapes of 5mC, 5hmC, and 6mA modifications in papillary thyroid carcinogenesis

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年6月17日

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  • Qingqing Li,
  • Jianli Yan,
  • Yulan Wang,
  • Fang Fang,
  • Mingquan Ye,
  • Wei Xu

摘要

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).