Genetic Mutations in Recurrent/Metastatic Papillary Thyroid Carcinoma.

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.