The Coexistence of Genetic Mutations in Thyroid Carcinoma Predicts Histopathological Factors Associated With a Poor Prognosis: A Systematic Review and Network Meta-Analysis

Purpose: Genetic mutations may play an important role in the progression and invasion of thyroid carcinoma (TC), and their coexistence may result in mutational synergy. The presence of the BRAF^V600E mutation, as well as mutations affecting the TERT promoter, RAS, CHEK2 and RET/PTC, may all have an impact on prognosis. The aim of this study was to explore whether synergy between the coexistent mutations predicts histopathological prognostic factors that influence disease outcome.

Methods: A comprehensive literature search of PubMed, Embase and the Cochrane Library, from their inception until January 2020. Primary outcomes included: disease stage, lymph node metastasis, extrathyroidal extension and distant metastasis; while, secondary outcomes included: tumor recurrence, mortality, invasion of thyroid capsule, multiplicity, presented as an odds ratio (OR) with 95% credible intervals (CrI).

Results: 27 publications (comprising 9 active intervention arms), involving 8,388 TC patients, were selected. Network meta-analytic estimates of active interventions contrasted with other active interventions, with random effects, were calculated. In terms of outcomes focus on overall TC, BRAF^V600E + TERT co-mutation ranked highest for diseases stage (OR = 5.74, 95% CrI: 3.09-10.66), as well as lymph node metastasis, extrathyroidal extension (5.74, 4.06-8.10), tumor recurrence (7.21, 3.59-14.47), and invasion of the thyroid capsule (3.11, 1.95-4.95). BRAF^V600E + TERT co-mutation ranked secondary in distant metastasis, mortality, and multiplicity that ranked highest was TERT+RAS or RAS. When we were limited to the study of patients with papillary TC (PTC), BRAF^V600E + TERT always ranked highest for primary outcomes: disease stage (6.39, 3.13-13.04), lymph node metastasis, extrathyroidal extension (5.80,3.89-8.64) and distant metastasis (7.33, 3.00-17.89), while BRAF^V600E + TERT again ranked highest in secondary outcomes: tumor recurrence (7.23,3.37-15.51), mortality (9.26, 3.02-28.42), invasion of thyroid capsule (3.20,2.01-5.11), and multiplicity.

Conclusions: In this molecular marker mutation-based systematic review and network meta-analysis, we found that coexistent BRAF^V600E + TERT genetic co-mutations predicted poor histopathological prognosis, including progression, invasion, and metastasis, especially in PTC. For the overall TC, the BRAF^V600E + TERT + RAS triple mutations may have a greater impact on the prognosis, and further research should related to potentially important features. This study is registered with PROSPERO, number CRD42019143242.