Genetic Mutations in Recurrent/Metastatic Papillary Thyroid Carcinoma

ABSTRACT Objectives The purpose of this study is to investigate the genetic mutational status of recurrent/metastatic papillary thyroid carcinoma (PTC) and its prognostic implications. Methods Data were analyzed for 348 consecutive patients with PTC registered at the Japan National Cancer Center, Center for Cancer Genomics and Advanced Therapeutics (C‐CAT) between June 2019 and February 2026. Genetic mutations were determined by next generation sequencing. Survival of patients was determined by log‐rank test and a Cox proportional hazards model. Results The top 10 mutations in recurrent/metastatic PTC were TERT (82.2%), BRAF (78.7%), LTK (16.1%), CDKN2A (15.2%), KMT2D (14.4%), NOTCH3 (14.1%), TP53 (12.9%), PIK3CA (11.5%), CDKN2B (10.6%), STK11 (10.3%), with 11.0 ± 0.19 (mean ± SEM) mutations/individual. BRAF ( p = 0.0379), CDKN2A ( p = 7.41 × 10 −12 ), KMT2D ( p = 0.0048), PIK3CA ( p = 0.0406), CDKN2B ( p = 7.24 × 10 −13 ), and concurrent TERT/BRAF ( p = 0.0141) were associated with a significantly worse prognosis, as determined by log‐rank test. Multivariable Cox proportional hazards analysis was 3.762 (95% CI, 1.7480–8.095; p = 7.026 × 10 −4 ) for CDKN2A , 2.620 (1.50–4.575; p = 7.076 × 10 −4 ) for KMT2D, 1.882 (1.127–3.143; p = 0.01572) for concurrent TERT/BRAF . Conclusions This study delineated the mutational spectrum of recurrent and/or metastatic PTC and identified several alterations with significant prognostic relevance. Even in advanced disease, specific mutations such as CDKN2A , KMT2D , and concurrent TERT/BRAF remained strongly associated with poor survival, underscoring the clinical value of comprehensive cancer genomic profiling in this population. Level of Evidence 3.