Effects of Coexistent BRAFV600Eand TERT Promoter Mutations on Poor Clinical Outcomes in Papillary Thyroid Cancer: A Meta-Analysis.
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 BRAFV600Emutation has been demonstrated. The aim of this study was to verify the role of this genetic duet in papillary thyroid cancer (PTC).



Studies of the association of BRAFV600Eand TERT promoter mutations with clinicopathologic features, recurrence, or PTC-related mortality were included from PubMed and Embase databases (inception to September 2016).



Thirteen eligible studies incorporating 4347 patients with PTC were included, and 283 (median 8.3%) of these patients had coexistent BRAFV600Eand 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. BRAFV600E: 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. BRAFV600E: OR = 3.1 [CI 2.2-4.37]; vs. TERT: OR = 5.66 [CI 3.02-10.6]), lymph node metastasis (vs. BRAFV600E: OR = 1.59 [CI 1.16-2.17]; vs. TERT: OR = 2.03 [CI 1.22-3.38]), and distant metastasis (vs. BRAFV600E: 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]; BRAFV600Evs. 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 BRAFV600Ealone (HR = 20.07 [CI 8.37-48.09]).



Coexistent BRAFV600Eand TERT promoter mutations have a synergistic effect on clinical outcomes in PTC, whereas each mutation alone has a modest effect. Therefore, molecular testing of BRAFV600Eand TERT promoter mutations together is useful in assessing risk stratification of PTC.
1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.
Shinje
S
Moon
1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.
Young Shin
YS
Song
1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.
Ye An
YA
Kim
1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.|2 Department of Internal Medicine, National Medical Center , Seoul, Korea.
Jung Ah
JA
Lim
1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.
Sun Wook
SW
Cho
1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.|3 Department of Internal Medicine, Seoul National University Bundang Hospital , Seongnam, Korea.
Jae Hoon
JH
Moon
4 Medical Research Collaborating Center, Seoul National University Hospital, Seoul, Korea.
Seokyung
S
Hahn
1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.
Do Joon
DJ
Park
1 Department of Internal Medicine, Seoul National University College of Medicine , Seoul, Korea.|5 Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.
Young Joo
YJ
Park
D002291:Carcinoma, Papillary / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D006801:Humans; D009154:Mutation; D011379:Prognosis; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology
D048493:Proto-Oncogene Proteins B-raf; D019098:Telomerase
BRAF mutation; TERT promoter mutation; mortality; papillary thyroid cancer; prognosis; recurrence