Endocrinol Metab.  2016 Mar;31(1):100-104. 10.3803/EnM.2016.31.1.100.

Low Prevalence of Somatic TERT Promoter Mutations in Classic Papillary Thyroid Carcinoma

• Jeon MJ
• Kim WG
• Sim S
• Lim S
• Kwon H
• Kim TY
• Shong YK
• Kim WB

• KMID: 2169699
• DOI: http://doi.org/10.3803/EnM.2016.31.1.100

Abstract

BACKGROUND
Transcriptional activating mutations of telomerase reverse transcriptase (TERT) are associated with more aggressive thyroid cancer. We evaluated the significance of TERT promoter mutations in Korean patients with classic papillary thyroid cancer (PTC).
METHODS
Genomic DNA was isolated from four thyroid cancer cell lines and 35 fresh-frozen PTC tissues. TERT promoter mutations (C228T and C250T) and the BRAF V600E mutation were evaluated by polymerase chain reaction amplification and direct sequencing.
RESULTS
The CC228229TT mutation in the TERT promoter was detected in BCPAP cells and the C250T mutation was found in 8505C cells. No TERT promoter mutation was observed in Cal-62 or ML-1 cells. The C228T mutation was found in only 1 of 35 (2.8%) PTCs and no C250T mutations were detected in any of the study subjects. The BRAF V600E mutation was found in 20 of 35 (57.1%) PTCs. One patient with the C228T TERT mutation also harbored the BRAF V600E mutation and developed a recurrence.
CONCLUSION
The prevalence of somatic TERT promoter mutations was low in Korean patients with classic PTC. Therefore, the prognostic role of TERT promoter mutations might be limited in this patient cohort.

Keyword

Thyroid cancer, papillary; Telomerase; Mutation

MeSH Terms

Cell Line
Cohort Studies
DNA
Humans
Polymerase Chain Reaction
Prevalence*
Recurrence
Telomerase
Thyroid Gland*
Thyroid Neoplasms*
DNA
Telomerase

Figure

• 

  Fig. 1 Direct sequencing results of the human transcriptional activating mutations of telomerase reverse transcriptase (TERT) promoter in thyroid cancer cell lines. (A) BCPAP cells had the CC228229TT mutation in the TERT promoter. (B) 8505C cells had the C250T and C253T mutations in the TERT promoter.

• 

  Fig. 2 Direct sequencing results of the human transcriptional activating mutations of telomerase reverse transcriptase (TERT) promoter in papillary thyroid cancer (PTC). (A) One patient with PTC had the C228T TERT promoter mutation. (B) Representative results of 34 PTCs with the wild-type TERT promoter.

Reference

1. Xing M, Haugen BR, Schlumberger M. Progress in molecular-based management of differentiated thyroid cancer. Lancet. 2013; 381:1058–1069.

2. Xing M. BRAF mutation in papillary thyroid cancer: pathogenic role, molecular bases, and clinical implications. Endocr Rev. 2007; 28:742–762.

3. Kim JG. Molecular pathogenesis and targeted therapies in well-differentiated thyroid carcinoma. Endocrinol Metab (Seoul). 2014; 29:211–216.

4. Xing M, Westra WH, Tufano RP, Cohen Y, Rosenbaum E, Rhoden KJ, et al. BRAF mutation predicts a poorer clinical prognosis for papillary thyroid cancer. J Clin Endocrinol Metab. 2005; 90:6373–6379.

5. Xing M, Alzahrani AS, Carson KA, Viola D, Elisei R, Bendlova B, et al. Association between BRAF V600E mutation and mortality in patients with papillary thyroid cancer. JAMA. 2013; 309:1493–1501.

6. Xing M, Alzahrani AS, Carson KA, Shong YK, Kim TY, Viola D, et al. Association between BRAF V600E mutation and recurrence of papillary thyroid cancer. J Clin Oncol. 2015; 33:42–50.

7. Kim TY, Kim WG, Kim WB, Shong YK. Current status and future perspectives in differentiated thyroid cancer. Endocrinol Metab (Seoul). 2014; 29:217–225.

8. Kim TH, Park YJ, Lim JA, Ahn HY, Lee EK, Lee YJ, et al. The association of the BRAF(V600E) mutation with prognostic factors and poor clinical outcome in papillary thyroid cancer: a meta-analysis. Cancer. 2012; 118:1764–1773.

9. Kim TY, Kim WB, Rhee YS, Song JY, Kim JM, Gong G, et al. The BRAF mutation is useful for prediction of clinical recurrence in low-risk patients with conventional papillary thyroid carcinoma. Clin Endocrinol (Oxf). 2006; 65:364–368.

10. Hong AR, Lim JA, Kim TH, Choi HS, Yoo WS, Min HS, et al. The frequency and clinical implications of the BRAF (V600E) mutation in papillary thyroid cancer patients in Korea over the past two decades. Endocrinol Metab (Seoul). 2014; 29:505–513.

11. Yim JH, Kim WG, Jeon MJ, Han JM, Kim TY, Yoon JH, et al. Association between expression of X-linked inhibitor of apoptosis protein and the clinical outcome in a BRAF V600E-prevalent papillary thyroid cancer population. Thyroid. 2014; 24:689–694.

12. Kim TY, Kim WB, Song JY, Rhee YS, Gong G, Cho YM, et al. The BRAF mutation is not associated with poor prognostic factors in Korean patients with conventional papillary thyroid microcarcinoma. Clin Endocrinol (Oxf). 2005; 63:588–593.

13. Kim NW, Piatyszek MA, Prowse KR, Harley CB, West MD, Ho PL, et al. Specific association of human telomerase activity with immortal cells and cancer. Science. 1994; 266:2011–2015.

14. Huang DS, Wang Z, He XJ, Diplas BH, Yang R, Killela PJ, et al. Recurrent TERT promoter mutations identified in a large-scale study of multiple tumour types are associated with increased TERT expression and telomerase activation. Eur J Cancer. 2015; 51:969–976.

15. Labussiere M, Di Stefano AL, Gleize V, Boisselier B, Giry M, Mangesius S, et al. TERT promoter mutations in gliomas, genetic associations and clinico-pathological correlations. Br J Cancer. 2014; 111:2024–2032.

16. Liu X, Bishop J, Shan Y, Pai S, Liu D, Murugan AK, et al. Highly prevalent TERT promoter mutations in aggressive thyroid cancers. Endocr Relat Cancer. 2013; 20:603–610.

17. Liu X, Qu S, Liu R, Sheng C, Shi X, Zhu G, et al. TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer. J Clin Endocrinol Metab. 2014; 99:E1130–E1136.

18. Melo M, da Rocha AG, Vinagre J, Batista R, Peixoto J, Tavares C, et al. TERT promoter mutations are a major indicator of poor outcome in differentiated thyroid carcinomas. J Clin Endocrinol Metab. 2014; 99:E754–E765.

19. Xing M, Liu R, Liu X, Murugan AK, Zhu G, Zeiger MA, et al. BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence. J Clin Oncol. 2014; 32:2718–2726.

20. Gandolfi G, Ragazzi M, Frasoldati A, Piana S, Ciarrocchi A, Sancisi V. TERT promoter mutations are associated with distant metastases in papillary thyroid carcinoma. Eur J Endocrinol. 2015; 172:403–413.