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The genetic landscape of distantly metastatic DTC (DMDTC) has not been well characterized in large cohorts. This study aimed to identify functional genetic alterations in DMDTC and validate their biological significance. We included 78 patients with DMDTC and performed DNA\u2010based next\u2010generation sequencing (NGS) in all cases, followed by RNA\u2010based NGS for fusion gene detection, along with a review of previously reported isolated cases. Plasmids harbouring novel variants, including\n                    <jats:italic>SPON1<\/jats:italic>\n                    ::\n                    <jats:italic>ALK<\/jats:italic>\n                    and\n                    <jats:italic>RFTN1<\/jats:italic>\n                    ::\n                    <jats:italic>BRAF<\/jats:italic>\n                    fusions, and mutations in\n                    <jats:italic>PTEN<\/jats:italic>\n                    (c.322_345del, c.740del, c.968dup),\n                    <jats:italic>STK11<\/jats:italic>\n                    (c.842C&gt;T, c.1225C&gt;T), and\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    (c.891G&gt;A, c.2312G&gt;A, c.2595A&gt;T, c.2606G&gt;A) were constructed and transfected into TPC\u20101 and HEK293T cells to investigate downstream signalling. The methylation status of differentially methylated genes (DMGs) associated with\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    mutations was analysed using the Infinium MethylationEPIC v2.0 BeadChip, with several DMGs validated by real\u2010time quantitative PCR. The cohort consisted of 25 males and 53 females, with a mean age of 60.3\u2009years at the diagnosis of metastasis. Histological 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\u2010free and overall survival. Genetic alterations involving phosphorylation signalling pathways were identified in 61 cases, among which pathological alterations of DNA damage repair (DDR)\u2010related genes were detected in ten cases. Novel\n                    <jats:italic>RFTN1<\/jats:italic>\n                    ::\n                    <jats:italic>BRAF<\/jats:italic>\n                    and\n                    <jats:italic>SPON1<\/jats:italic>\n                    ::\n                    <jats:italic>ALK<\/jats:italic>\n                    fusions, along with\n                    <jats:italic>PTEN<\/jats:italic>\n                    (c.740del, c.968dup) and\n                    <jats:italic>STK11<\/jats:italic>\n                    (c.842C&gt;T) mutations, could enhance downstream phosphorylation levels.\n                    <jats:italic>DNMT3A<\/jats:italic>\n                    mutations (c.891G&gt;A, c.2312G&gt;A, c.2595A&gt;T, c.2606G&gt;A) induced genome\u2010wide methylation dysregulation, with altered expression of\n                    <jats:italic>SLC12A7<\/jats:italic>\n                    ,\n                    <jats:italic>FLNC<\/jats:italic>\n                    ,\n                    <jats:italic>HMGB2<\/jats:italic>\n                    ,\n                    <jats:italic>BNC2<\/jats:italic>\n                    , and\n                    <jats:italic>DAPK1<\/jats:italic>\n                    . This study shows that DMDTCs are characterized by dysregulated phosphorylation signalling, accompanied by chromosomal instability and aberrant methylation, thus underscoring DDR gene\u2010targeted therapy as a promising strategy. \u00a9 2026 The Pathological Society of Great Britain and Ireland.\n                  <\/jats:p>","DOI":"10.1002\/path.70052","type":"journal-article","created":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T03:34:42Z","timestamp":1774496082000},"page":"284-296","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Distantly metastatic differentiated thyroid carcinoma is kinase\u2010driven and enriched for\n                    <scp>DNA<\/scp>\n                    repair and\n                    <scp>DNA<\/scp>\n                    methylation gene alterations"],"prefix":"10.1002","volume":"269","author":[{"given":"Weimao","family":"Kong","sequence":"first","affiliation":[{"name":"Department 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