Abstract
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Purpose: Genetic mutations play important roles in not only development of papillary thyroid carcinoma (PTC) but also determination of its properties. The radioactive iodine refractory (RAIR) state is a harbinger of a poor outcome of PTC. We used various statistical models to investigate the significance of the TERT promoter, BRAF, and RAS mutations in distinguishing RAIRness and their relationships with 131I uptake.
Methods: The TERT promoter, BRAF, and RAS mutations were examined in primary lesions of 33 RAIR cases and age and sex-matched 34 131I-treated cases with disease-free status. Thyrotropin-stimulated thyroglobulin (sTg) change, 131I uptake ability, and RAIR categories were evaluated in the RAIR cases.
Results: The prevalence of the TERT mutation in the RAIR group was 24.24% (8/33), which was significantly higher than that in the disease-free group (0/34). The BRAF mutation showed high prevalence in both the RAIR group (69.70%) and the cured group (64.71%) without significant difference. Among the eight TERT mutation-positive cases, six had the TERT/BRAF double mutation. The RAS mutation was detected in only one cured case and two RAIR cases. Despite the significantly higher prevalence of the TERT mutation in the RAIR group, only tumor size and N1b lymph node involvement were independently associated with the RAIR status. When we focused on the RAIR group, all the patients with the TERT mutation showed maximum or increased sTg. Multivariate analyses demonstrated that the TERT mutation was associated with decreased 131I uptake and the RAIR categories of absent or weaker 131I uptake.
Conclusions: The TERT mutation constitutes a novel genetic pattern indicating absent or weaker 131I-avid lesions in RAIR PTC. Further studies using properly matched cases are necessary to gain a better understanding of the independent impact of the TERT mutation on differentiating the RAIR PTC from the disease-free PTC. Figure legends Figure 1. Serological thyrotropin stimulated thyroglobulin (sTg) response to 131I therapy in tumors with different mutation status. Figure 2. Box-and-whisker plots of tumor-to-background (T/B) ratio, calculated in all 131I refractory cases at the initial therapy (empty box for T/B1) and after the subsequent 131I therapy (filled box for T/B2) using SPECT/CT region-of-interest software. Results of statistical comparisons by Wilcoxon signed-rank test are indicated for each pair; NS - not significant. Figure 3. Representative cases with different mutational status of primary lesion. (A) A 51-year old female patient with non-131I-avid deep cervical LN metastases and non-131I-avid pulmonary metastases had the TERT/BRAF double mutation. (B) A 77-year old male patient with non-131I-avid pulmonary metastases had the TERT mutation only. (C) A 62-year old female patient with 131I-avid deep cervical LN metastases but non-131I-avid pulmonary metastases had the BRAF mutation only. (D) A 32-year old female patient with 131I-avid deep cervical LN metastases and 131I-avid pulmonary metastases had no mutation.
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