Association of DNA Promoter Methylation and Mutation in Thyroid Cancer.

The V600E mutation and DNA promoter methylation play important roles in the pathogenesis of thyroid cancer (TC). However, the association of these genetic and epigenetic alterations is not clear. In this study, using paired tumor and surrounding normal tissue from the same patients, on a genome-wide scale we tried to identify (a) any association between mutation and DNA promoter methylation, and (b) if the molecular findings may provide a basis for therapeutic intervention. We included 40 patients with TC (female = 28, male = 12) without distant metastasis. mutation was present in 18 cases. We identified groups of differentially methylated loci (DML) that are found in (a) both mutant and wild type, (b) only in mutant tumors, and (c) only in wild type. BRAF mutation-specific promoter loci were more frequently hypomethylated, whereas BRAF wild-type-specific loci were more frequently hypermethylated. Common DML were enriched in cancer-related pathways, including the mismatch repair pathway and Wnt-signaling pathway. Wild-type-specific DML were enriched in RAS signaling. Methylation status of checkpoint signaling genes, as well as the T-cell inflamed genes, indicated an opportunity for the potential use of inhibitors in BRAF mutant TC. Our study shows an association between mutation and methylation in TC that may have biological significance.