TERT is the catalytic subunit of telomerase, which plays an important role in cell immortalization and tumorigenesis. The two TERT promoter mutations were shown to be mutually exclusive and able to increase TERT expression [20, 21]. They were also shown to be associated with aggressiveness of other human cancers, such as melanoma, brain tumor, bladder cancer and papillary thyroid carcinoma [22–26]. The prevalence of TERT promoter mutations in PTC varied between 7.5–27% in previous studies [26–33]. In our last report about rs2736100, the TERT rs2736100 genetic variant (TG/GG versus TT) is significantly associated with elevated PTC risk. Correlations between rs2736100 genotypes and tissue-specific TERT expression supported the regulatory function of this genetic variant in vivo. Our data demonstrated that the functional TERT rs2736100 SNP was a novel genetic component of PTC etiology .However, whether genetic variants of TERT-CLPTM1L are associated with the increased risk of PTC in clinical is unknown.
Some studies showed an association between BRAF V600E and TERT promoter mutations. In Xing`s study, coexistence of the two mutations was associated with the worst clinicopathological outcomes of PTC . The TERT C228T alone was significantly associated with lymph node metastasis, and there was an insignificantly association with other clinicopathological characteristics. In contrast, the coexistence of BRAF V600E and TERT C228T was strongly associated with virtually all the high-risk characteristics as well as distant metastasis recurrence. In the survival analysis, similar result demonstrated that TERT mutation only cannot affect the disease-free survival over than the coexistence of BRAF V600E and TERT C228T. The similar results were demonstrated in several reports; the coexistence of BRAF V600E and TERT promoter mutations was particularly associated with high-risk clinicopathological features [28, 34–38]. Those reports that implied the effects of TERT C228T mutation fell short of significant when it was separated from the BRAF mutation and have been examined alone, suggested that the TERT mutation needs additional genetic alteration to cooperate to promote the aggressive of PTC. However, in Melo`s reports which detected an association between TERT mutations and aggressive clinicopathological features and had enough evidence to state that TERT promoter mutations with or without BRAF V600E was major indicator of poor prognosis in differentiated thyroid cancer and notably in PTC, due to its association with distant metastasis and increased disease specific mortality [26, 39, 40]. Unfortunately, the BRAF status was not assessed in this research. Additionally, the TERT rs2736100 mutations coexistence with/without the BRAF V600E is particularly associated with some high-risk clinicopathological features, but unassociated with prognosis much on PTC patients in this research.
Additionally, the overall recurrence (recurrence of lymph nodes and neo-distant metastases were combined as an end-point event) was 100 of 264 in mutation positive patients versus 37 of 99 in mutation negative patients. The recurrence was related with large size (p = 0.000 OR = 3.039 95% C.I. 1.955–4.724) and younger age (p = 0.046 OR = 0.656 95% C.I. 0.434–0.992 for AGE > 45y) after logistic regression. However, the TERT rs2736100 genetic polymorphism was unrelated to the recurrence, neo-distant metastasis and end-point event in this study.
There were several reports focus on the SNP re2736100. In Liu`s study, only rs2736100 was significantly (P = 0.034) associated with an increased risk of lung cancer and suggested that rs2736100 on TERT-CLPTM1L indicates a poor prognosis for lung cancer in the Chinese Han population . In Bae`s report, The single-nucleotide polymorphisms (SNP) at 5p15 (rs2736100, adjusted odds ratio 1.32, 95% confidence interval [CI] 1.03–1.67, P = 0.025) were significantly associated with lung cancer risk . In Simon`s report indicated that the SNP rs2736100 risk genotypes were highly correlated with high-grade disease (P < 0.001), but the rs2736100 unrelated with prognosis of tumor grade in glioma independently . In Choi`s study, there was no significant difference between the patients with gastric cancer and healthy controls in the genotype and allele frequencies of the rs2736100 polymorphism. The rs2736100 polymorphism of the hTERT gene is involved in the regulation of hTERT expression and telomere length, but not in the risk of gastric cancer . In Chen`s report, for rs2736100, the G variant and the GG genotype were more frequent, whereas the TT genotype was less frequent in patients with lung adenocarcinoma than in controls. They suggested that multiple variants at 5p15.33 contribute to susceptibility to lung adenocarcinoma . In those reports, only Liu`s report demonstrate the SNP re2736100 significantly related with poor prognosis, the others show that the SNP rs2736100 was only related with several high risk clinicopathological features excluding poor prognosis. Our result agrees well with those report with the overall recurrence-free (recurrence of lymph nodes and neo-distant metastases were combined as an end-point event) survival un-affected significantly of patients with PTC.
In our recent study, we observed that the TERT rs2736100 mutation (either TG or GG) were significantly associated with some high risk clinicopathological features such as tumor spread, extra-thyroidal extension, central/lateral lymph node metastases, stage T III and IV disease. In the multivariate analysis, the TERT rs2736100 mutation was significantly associated with extra-thyroidal extension only (p = 0.004 OR = 1.832 95% C.I. 1.217–2.757). However, in the Kaplan-Meier survival analysis, the rs2376100 mutation was unrelated to the overall disease-free survival with log-rank p > 0.05. In the Cox-regression analysis, the overall survival rate of recurrence was related with lager size of tumor (p = 0.002 RR = 1.983 95% C.I. 1.296–3.034), younger age (p = 0.050 OR = 0.671 95% C.I. 0.451-1.000 for AGE > 45y) and tumor spread (p = 0.023 RR = 1.582 95% C.I. 1.064–2.352) and unrelated with rs2376100 mutation and the others.
The TERT mutation result is similar with Myung`s report . No significant difference in the frequency of the TERT promoter mutation was observed between the recurrence/metastasis group and the non-recurrence/metastasis group. These results suggest that the prognostic implications of the TERT promoter mutation are dependent on clinicopathological features. Additional, In Gong`s report, the hTERT gene polymorphism at rs10069690 C/T is associated with the risk and prognosis of thyroid cancer, but hTERT gene polymorphism at rs2736100G/T is not . Our results agree well with these reports.
The papillary thyroid carcinoma histotypes carries in general a good or even an excellent prognosis. The TERT rs2736100 mutation-positive PTC is more likely to manifest with aggressive clinicopathological characteristics. In appropriate clinical settings, testing for the TERT rs2736100 mutation-positive is likely to be useful in assisting the risk stratification and management of PTC, but not to predict prognosis in clinical practices . These recent findings on TERT rs2736100 mutation-positive in thyroid cancer are exciting, but they remain to be confirmed and generalized by further and high-power studies, ideally in different ethnic populations.