Effects of Coexistent BRAF and TERT Promoter Mutations on Poor Clinical Outcomes in Papillary Thyroid Cancer: A Meta-Analysis.

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 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 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 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: 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: OR = 3.1 [CI 2.2-4.37]; vs. TERT: OR = 5.66 [CI 3.02-10.6]), lymph node metastasis (vs. BRAF: OR = 1.59 [CI 1.16-2.17]; vs. TERT: OR = 2.03 [CI 1.22-3.38]), and distant metastasis (vs. BRAF: 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 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 alone (HR = 20.07 [CI 8.37-48.09]).

CONCLUSIONS

Coexistent BRAF 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 and TERT promoter mutations together is useful in assessing risk stratification of PTC.