Regulatory Single Nucleotide Polymorphism Increases <b><i>TERT</i></b> Promoter Activity in Thyroid Carcinoma Cells

Abstract

&lt;b&gt;&lt;i&gt;Background/Aim:&lt;/i&gt;&lt;/b&gt; The telomerase reverse transcriptase (&lt;i&gt;TERT&lt;/i&gt;) promoter has a regulatory single nucleotide polymorphism (rSNP), rs2853669, and occasionally shows point mutations C228T and C250T. Although C228T and C250T have been well examined to increase &lt;i&gt;TERT&lt;/i&gt; promoter activity and are known as risk factors for thyroid carcinoma, the significance of rs2853669 has not been well investigated. This study aimed to clarify the influence of rs2853669 on &lt;i&gt;TERT&lt;/i&gt; promoter activity in thyroid carcinoma cells. &lt;b&gt;&lt;i&gt;Materials:&lt;/i&gt;&lt;/b&gt; Seven of 8 examined thyroid cell lines had rs2853669, 5 had C228T, and 1 had C250T. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Three papillary thyroid carcinoma cell lines, harboring both rs2853669 and C228T, showed higher &lt;i&gt;TERT&lt;/i&gt; mRNA expression on real-time PCR than the other cell lines. Anaplastic thyroid carcinoma cell lines, in contrast, showed variable &lt;i&gt;TERT&lt;/i&gt; mRNA expression depending on the combination of rs2853669, C228T, and C250T. Luciferase assays, performed to compare the influences of rs2853669, C228T, and C250T on &lt;i&gt;TERT&lt;/i&gt; promoter activity in thyroid carcinoma, showed that rs2853669, as well as C228T, increased the promoter activity, and the combination of rs2853669 and C228T increased the promoter activity even more strongly than C228T alone. &lt;b&gt;&lt;i&gt;Conclusion:&lt;/i&gt;&lt;/b&gt; We conclude that the presence of rs2853669 within the &lt;i&gt;TERT&lt;/i&gt; promoter could be as significant as the C228T mutation in thyroid carcinoma.

Lymph Node Metastasis in Papillary Thyroid Carcinoma, A Study of BRAF V600E and TERT Promoter Mutations

“…In contrast, a previous study in Japanese patients found that there was a significant relationship between the coexistence of TERT rs2853669 and C288T mutations and larger tumor sizes (p > 0.01) and a higher TERT promoter activity compared to single C288T or rs2853669 mutations [7,30]. In addition, the activity of TERT promoter in rs2853669 mutation was discovered to be higher than in C250T mutation.…”

“…Most of these genetic changes occur in the Mitogen-Activate protein kinase (MAPK) pathway, including RET/PTC rearrangement (20-40%), BRAF mutations (45%) and RAS (10-20%) [5,6]. Aside from that, there are several TERT markers which have been researched in the last five years and show an important role in the pathogenesis of thyroid cancer, including the C228T mutation, C250T mutation, and rs2853669 in the telomerase reverse transcriptase (TERT) gene [7].…”

<i>TERT</i> promoter mutations in thyroid cancer

“…Regarding the difference between the -124 and -146 mutations, several papers have reported that the transcriptional activity of -124 was higher than -146 in reporter assays [3][4][5][6][7], while others demonstrated no difference [1,8]. As enhancers strongly regulate transcription of the human TERT gene, reporter assays using only the promoter region may not be able to reach a conclusion [9].…”