Background: The presence of a telomerase reverse transcriptase (TERT) promoter mutation has been suggested as a potential prognostic marker for thyroid cancer, and a synergistic association with the BRAF^V600E mutation has been demonstrated. The aim of this study was to verify the role of this genetic duet in papillary thyroid cancer (PTC).

Methods: Studies of the association of BRAF^V600E and TERT promoter mutations with clinicopathologic features, recurrence, or PTC-related mortality were included from PubMed and Embase databases (inception to September 2016).

Results: Thirteen eligible studies incorporating 4347 patients with PTC were included, and 283 (median 8.3%) of these patients had coexistent BRAF^V600E and TERT promoter mutations. The coexistence of the two mutations was far more strongly associated with high-risk clinicopathologic features than either mutation alone was, including advanced TNM stage (vs. BRAF^V600E: odds ratio [OR] = 4.19 [confidence interval (CI) 3.07–5.71]; vs. TERT: OR = 4.66 [CI 2.67–8.13]), extrathyroidal extension (vs. BRAF^V600E: OR = 3.1 [CI 2.2–4.37]; vs. TERT: OR = 5.66 [CI 3.02–10.6]), lymph node metastasis (vs. BRAF^V600E: OR = 1.59 [CI 1.16–2.17]; vs. TERT: OR = 2.03 [CI 1.22–3.38]), and distant metastasis (vs. BRAF^V600E: OR = 11.76 [CI 5.63–24.58]). The coexistence of the mutations showed the highest risk of recurrence (coexistence vs. no mutations: hazard ratio [HR] = 6.60 [CI 3.82–11.40]; BRAF^V600E vs. no mutations: HR = 1.31 [CI 0.49–3.46]; TERT vs. no mutations: HR = 3.38 [CI 0.85–13.35]). Moreover, PTC-related mortality was significantly higher with coexistent mutations than in the presence of BRAF^V600E alone (HR = 20.07 [CI 8.37–48.09]).

Conclusions: Coexistent BRAF^V600E and TERT promoter mutations have a synergistic effect on clinical outcomes in PTC, whereas each mutation alone has a modest effect. Therefore, molecular testing of BRAF^V600E and TERT promoter mutations together is useful in assessing risk stratification of PTC.