Effects of Coexistent BRAFV600E and TERT Promoter Mutations on Poor Clinical Outcomes in Papillary Thyroid Cancer: A Meta-Analysis

Shinje Moon; Young Shin Song; Ye An Kim; Jung Ah Lim; Sun Wook Cho; Jae Hoon Moon; Seokyung Hahn; Do Joon Park; Young Joo Park

doi:10.1089/thy.2016.0350

Effects of Coexistent BRAF^V600E and TERT Promoter Mutations on Poor Clinical Outcomes in Papillary Thyroid Cancer: A Meta-Analysis

Thyroid. 2017 May;27(5):651-660. doi: 10.1089/thy.2016.0350. Epub 2017 Mar 7.

Authors

Shinje Moon¹, Young Shin Song¹, Ye An Kim¹, Jung Ah Lim^{1

2}, Sun Wook Cho¹, Jae Hoon Moon^{1

3}, Seokyung Hahn⁴, Do Joon Park¹, Young Joo Park^{1

5}

Affiliations

¹ 1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.
² 2 Department of Internal Medicine, National Medical Center , Seoul, Korea.
³ 3 Department of Internal Medicine, Seoul National University Bundang Hospital , Seongnam, Korea.
⁴ 4 Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea.
⁵ 5 Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.

PMID: 28181854
DOI: 10.1089/thy.2016.0350

Abstract

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.

Keywords: BRAF mutation; TERT promoter mutation; mortality; papillary thyroid cancer; prognosis; recurrence.

Publication types

Meta-Analysis
Research Support, Non-U.S. Gov't

MeSH terms

Carcinoma, Papillary / genetics*
Carcinoma, Papillary / mortality
Carcinoma, Papillary / pathology
Humans
Mutation*
Prognosis
Promoter Regions, Genetic*
Proto-Oncogene Proteins B-raf / genetics*
Telomerase / genetics*
Thyroid Neoplasms / genetics*
Thyroid Neoplasms / mortality
Thyroid Neoplasms / pathology

Substances

Proto-Oncogene Proteins B-raf
Telomerase