The Genetic Duet of BRAF V600E and TERT Promoter Mutations Robustly Predicts Loss of Radioiodine Avidity in Recurrent Papillary Thyroid Cancer

Abstract

BRAF V600E and TERT promoter mutations, particularly their genetic duet, are well known to be associated with poor clinical outcomes of papillary thyroid cancer (PTC). Loss of radioactive iodine (RAI) avidity in recurrent PTC is a major cause of treatment failure and hence poor clinical outcomes. This study investigated the role of mutation patterns in loss of RAI avidity in recurrent PTC. Methods: This was a retrospective study of the relationship between loss of RAI avidity in structural recurrent PTC and the genotype patterns of BRAF V600E and TERT promoter mutations in 164 patients (104 women and 60 men) with a median age of 50 y (interquartile range, 35-62 y). Results: The overall prevalence of RAI avidity loss in recurrent PTC was 62.8% (103/164). When the cohort was divided into mutation and wild-type groups, the RAI avidity loss was 80.4% versus 33.9% (P , 0.001) in BRAF V600E versus wild-type BRAF patients, with an adjusted odds ratio of 7.11 (95% confidence interval [CI], 3.24-16.27), and 89.4% versus 52.1% (P , 0.001) in TERT mutation versus wildtype patients, with an adjusted odds ratio of 6.89 (95% CI, 2.28-25.66). When the cohort was divided into 4 genotypes, the RAI avidity loss was 70.3% (45/64), 55.6% (5/9), and 97.4% (37/38) in patients with BRAF V600E alone, TERT mutation alone, and the genetic duet of coexisting BRAF and TERT mutations, versus 30.2% (16/53) in patients with neither mutation (P , 0.001, 5 0.251, and , 0.001, respectively). These corresponded to odds ratios of 5.39 (95% CI, 2.31-13.13), 2.84 (95% CI, 0.53-16.32), and 81.04 (95% CI, 11.67-3559.83), respectively. The synergy index was 13.28 (95% CI, 1.54-114.46; P 5 0.019) between BRAF V600E and TERT mutation in cooperatively affecting RAI avidity. A similar genotype-associated expression pattern was observed for thyroid iodide-handling genes. Conclusion: BRAF V600E alone and, particularly, coexisting BRAF V600E and TERT promoter mutations are strongly associated with loss of RAI avidity and impairment of the iodide-metabolizing machinery in recurrent PTC, showing a robust predictive value for failure of RAI treatment of PTC.

PIWI-interacting RNAs piR-13643 and piR-21238 are promising diagnostic biomarkers of papillary thyroid carcinoma

“…A search of the TCGA-THCA database identified and characterized > 96% of driver mutations of PTC, finding BRAF (mutation in 59.7% PTC), NRAS (mutation in 8.5% PTC) and HRAS (mutation in 3.5% PTC) as the most common causative genes [33,34]. Our data are consistent with previous studies confirming that BRAF V600E gene mutation is important in the diagnosis of PTC [35][36][37]. However, BRAF also has been reported to mutate in benign thyroid nodules and is not suitable for early diagnosis of thyroid cancer [30,38,39].…”

Clinical, Pathological, and Molecular Characteristics Correlating to the Occurrence of Radioiodine Refractory Differentiated Thyroid Carcinoma: A Systematic Review and Meta-Analysis

“…Forty-six remaining studies were retrieved for assessment, and a flow chart showed the process of literature retrieval (Figure 1). Of 13 eligible articles, 12 were retrospective studies, and one study from China was prospective (7)(8)(9)(10)(11)(12)(13)(14)(15)(16)(17)(18)(19). Two appropriate reports were included, although they were conference abstracts.…”

<i>BRAF</i> and <i>TERT</i> promoter mutations: clinical application in thyroid cancer

“…Concomitant BRAF and TERT promoter mutations worsened the survival rate of patients with PTC (10-year survival, both mutations 83% vs. wild type 99%; HR 5.62). Recently, Liu et al reported that coexisting BRAF and TERT promoter mutations are strongly associated with the loss of RAI avidity in recurrent PTC, showing a robust predictive value for failure of RAI treatment of PTC [85]. Thereafter, several studies have supported the synergistic effects of concomitant BRAF and TERT promoter mutations [78,[86][87][88].…”