TERT Promoter Mutations Increase Tumor Aggressiveness by Altering TERT mRNA Splicing in Papillary Thyroid Carcinoma

Author:

Sako Ayaka12,Matsuse Michiko1,Saenko Vladimir3ORCID,Tanaka Aya4,Otsubo Ryota4,Morita Michi5,Kuba Sayaka5,Nishihara Eijun6ORCID,Suzuki Keiji1ORCID,Ogi Tomoo7,Kawakami Atsushi8,Mitsutake Norisato13ORCID

Affiliation:

1. Department of Radiation Medical Sciences, Nagasaki University , Nagasaki 852-8523 , Japan

2. Department of Endocrinology and Metabolism , Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki 852-8501 , Japan

3. Department of Radiation Molecular Epidemiology, Atomic Bomb Disease Institute, Nagasaki University , Nagasaki 852-8523 , Japan

4. Department of Surgical Oncology, Graduate School of Biomedical Sciences, Nagasaki University , Nagasaki 852-8501 , Japan

5. Department of Surgery, Graduate School of Biomedical Sciences, Nagasaki University , Nagasaki 852-8501 , Japan

6. Department of Internal Medicine, Kuma Hospital, Kobe 650-0011, Japan

7. Department of Genetics, Research Institute of Environmental Medicine, Nagoya University , Nagoya 464-8601 , Japan

8. Department of Immunology and Rheumatology, Graduate School of Biomedical Sciences, Nagasaki University , Nagasaki 852-8501 , Japan

Abstract

Abstract Context Telomerase reverse transcriptase promoter (TERT-p) mutations, which upregulate TERT expression, are strongly associated with tumor aggressiveness and worse prognosis in papillary thyroid carcinomas (PTCs). TERT expression is also observed in a proportion of PTCs without TERT-p mutations, but such tumors show less aggressiveness and better prognosis than TERT-p mutation–positive tumors. Objective TERT has multiple splicing variants whose relationships with the TERT-p status and clinicopathological characteristics remain poorly understood. We examined the relationship between the TERT-p mutational status, the TERT splicing pattern, and clinicopathological features. Methods We investigated the expression of 2 major variants, α deletion (dA) and β deletion (dB), in a series of 207 PTCs operated on between November 2001 and March 2020 in Nagasaki University Hospital and Kuma Hospital. Results The TERT-p mutations were found in 33 cases, and among 174 mutation-negative cases, 24 showed TERT expression. All cases were classified into 3 groups: the TERT-p mutation–negative/expression–negative group (mut−/exp−), the TERT-p mutation–negative/expression–positive group (mut−/exp+), and the TERT-p mutation–positive group (mut+/exp+). The +A+B/dB ratio in mut+/exp+ was significantly higher than that in mut−/exp+ PTCs. Analysis with clinicopathological data revealed that +A+B expression was associated with higher PTC aggressiveness, whereas dB expression counteracted this effect. Functional in vitro study demonstrated that dB strongly inhibited cell growth, migration, and clonogenicity, suggesting its tumor-suppressive role. Conclusion These results provide evidence that the TERT-p mutations alter the expression of different TERT splice variants, which, in turn, associates with different tumor aggressiveness.

Funder

JSPS KAKENHI

Nagasaki University

Publisher

The Endocrine Society

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