DNA Methylation Dynamics and Prognostic Implications in Metastatic Differentiated Thyroid Cancer

Area of Science:

• Oncology
• Epigenetics
• Genomics

Background:

• Distant metastases (DM) are the primary cause of differentiated thyroid cancer (DTC) mortality.
• The DNA methylation landscape in metastatic DTC and DM is not fully understood.
• Investigating methylation dynamics is crucial for understanding DTC progression.

Purpose of the Study:

• To investigate DNA methylation changes during DTC progression from primary tumors to DM.
• To identify potential clinical implications of these methylation alterations.
• To assess the prognostic value of a DNA methylation signature for DM development.

Main Methods:

• Multicenter retrospective study profiling DNA methylation in normal, non-metastatic, and metastatic DTC samples.
• Discovery cohort (97 samples) and validation cohort (30 samples) used.
• Receiver operating characteristic curve analysis applied to evaluate a prognostic CpG signature.

Main Results:

• DNA methylation alterations, predominantly hypomethylation, increased progressively from primary tumors to DM in both papillary (PTC) and follicular (FTC) thyroid carcinomas.
• Metastatic tumors showed a convergence of epigenetic changes, with higher overlap of differentially methylated CpGs (DMe-CpGs) between mPTC and mFTC.
• A validated 156-CpG signature in primary tumors distinguished non-metastatic from metastatic DTC, showing prognostic value for DM development.

Conclusions:

• Progressive DNA methylation alterations, mainly hypomethylation, occur during PTC and FTC metastatic progression.
• DM likely originates from a major subclone of the primary tumor, supported by de novo DMe-CpGs found in DM.
• The 156-CpG signature may identify high-risk DTC patients for DM, enabling personalized treatment strategies.