Distantly metastatic differentiated thyroid carcinoma is kinase-driven and enriched for DNA repair and DNA methylation gene alterations

Methylation status of differentially methylated genes (DMGs) associated with DNMT3A mutations was analysed using the Infinium Methylation EPIC v2.0 BeadChip, with several DMGs validated by quantitative real-time PCR. The cohort consisted of 25 males and 53 females, with a mean age of 60.3 years at the diagnosis of metastasis. Histologic types included papillary carcinoma (31 cases), follicular carcinoma (44 cases), and oncocytic carcinoma (3 cases).

The lung and bone were the most common metastatic sites. Multiple metastases and older age were associated with metastasis-free and overall survival. Genetic alterations involving phosphorylation signalling pathways were identified in 61 cases, among which pathologic alterations of DNA damage repair (DDR)-related gene were detected in 10 cases.

Novel RFTN1::BRAF and SPON1::ALK fusions, along with PTEN (c.740del, c.968dup) and STK11 (c.842C>T) mutations, could enhance down streaming phosphorylation levels. DNMT3A mutations (c.891G>A, c.2312G>A, c.2595A>T, c.2606G>A) induced genome-wide methylation dysregulation, with altered expressions of SLC12A7, FLUC, HMGB2, BNC2, and DAPK1. This study shows that DMDTCs are characterized by dysregulated phosphorylation signalling, accompanied by chromosomal instability and aberrant methylation, thus underscoring DDR gene-targeted therapy as a promising strategy.