| Summary: | Papillary thyroid carcinoma (PTC) usually presents an excellent prognosis, but some patients present with aggressive metastatic disease. BRAF, RAS, and TERT promoter (TERTp) genes are altered in PTC, and their impact on patient outcomes remains controversial. We aimed to determine the role of genetic alterations in PTC patient outcomes (recurrent/persistent disease, structural disease, and disease-specific mortality (DSM)). The series included 241 PTC patients submitted to surgery, between 2002–2015, in a single hospital. DNA was extracted from tissue samples of 287 lesions (primary tumors and metastases). Molecular alterations were detected by Sanger sequencing. Primary tumors presented 143 BRAF, 16 TERTp, and 13 RAS mutations. Isolated TERTp<sup>mut</sup> showed increased risk of structural disease (HR = 7.0, <i>p </i>< 0.001) and DSM (HR = 10.1, <i>p </i>= 0.001). Combined genotypes, BRAF<sup>wt</sup>/TERTp<sup>mut</sup> (HR = 6.8, <i>p </i>= 0.003), BRAF<sup>mut</sup>/TERTp<sup>mut</sup> (HR = 3.2, <i>p </i>= 0.056) and BRAF<sup>mut</sup>/TERTp<sup>wt</sup> (HR = 2.2, <i>p </i>= 0.023) showed increased risk of recurrent/persistent disease. Patients with tumors BRAF<sup>wt</sup>/TERTp<sup>mut</sup> (HR = 24.2, <i>p </i>< 0.001) and BRAF<sup>mut</sup>/TERTp<sup>mut</sup> (HR = 11.5, <i>p </i>= 0.002) showed increased risk of structural disease. DSM was significantly increased in patients with TERTp<sup>mut</sup> regardless of BRAF status (BRAF<sup>mut</sup>/TERTp<sup>mut</sup>, log-rank <i>p </i>< 0.001; BRAF<sup>wt</sup>/TERTp<sup>mut</sup>, log-rank <i>p </i>< 0.001). Our results indicate that molecular markers may have a role in predicting PTC patients’ outcome. BRAF<sup>mut</sup>/TERTp<sup>wt</sup> tumors were prone to associate with local aggressiveness (recurrent/persistent disease), whereas TERTp<sup>mut</sup> tumors were predisposed to recurrent structural disease and DSM.
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