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The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas

Oncogene volume 33, pages 4978–4984 (2014)Cite this article

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Abstract

Telomerase activation through induction of its catalytic component telomerase reverse transcriptase (TERT) expression is essential for malignant transformation. TERT promoter mutations namely C228T and C250T that stimulate TERT transcription and telomerase activation have recently been identified in many human malignancies. We thus determined these mutations and their biological and clinical implications in thyroid carcinomas in the present study. The TERT promoter was sequenced in 10 thyroid cancer cell lines and 144 tumors from 20 patients with anaplastic thyroid carcinoma (ATC), 51 with papillary thyroid carcinoma (PTC), 36 with follicular thyroid carcinoma (FTC), and 37 with medullary thyroid carcinoma (MTC). We identified C228T or C250T mutation in 6/8 of ATC cell lines, as well as in tumor tissue from 10/20, 13/51, 8/36 and 0/37 patients with ATC, PTC, FTC and MTC, respectively. In PTC patients, these mutations were exclusively present in the group with age >45 years (P<0.0001), and highly correlated shorter telomeres (P<0.0001) and distant metastasis (P=0.028). The previous radioactivity exposure did not induce the mutation. The presence of C228T or C250T was an independent predictor associated with shorter disease-related survival (DRS) in the entire cohort (P<0.0001), as well as among patients >45 years (P=0.021). ATC patients carrying the mutation survived shorter than those without mutations, although not statistically significant (P=0.129). The TERT promoter mutation was associated with overall survival (P=0.038) and DRS (P=0.058) of FTC patients. Taken together, age- and shorter telomere-dependent TERT promoter mutations occur frequently in follicular cell-derived thyroid carcinoma (ATC, PTC and FTC) but not in parafollicular cell-originated MTC, and may serve as a marker for aggressive disease and poor outcome.

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Acknowledgements

We thank Drs N-E Heldin (Uppsala University, Sweden), and BG Robinson and Mr. E Wennerberg (University of Sydney, Australia) for cell lines. The study was funded by grants from the Swedish Cancer Society, the Swedish Research Council, Cancer Society in Stockholm, the Stockholm County Council and Karolinska Institutet. Dr M Hulchiy (Kyiv CIty Teaching Endocrinological Center, Ukraine) for help with retrieval of Ukraine PTC tissue samples.

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  1. T Liu and N Wang: These authors contributed equally to this work.

Authors and Affiliations

  1. Division of Hematology and Center for Molecular Medicine, Department of Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden

    T Liu & D Xu

  2. Department of Oncology-Pathology and Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden

    N Wang, A Sofiadis & C Larsson

  3. Department of Women's and Children's Health and Center for Molecular Medicine, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden

    J Cao

  4. Department of Molecular Medicine and Surgery, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden

    A Dinets & J Zedenius

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  1. T Liu
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Correspondence to C Larsson or D Xu.

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Liu, T., Wang, N., Cao, J. et al. The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas. Oncogene 33, 4978–4984 (2014). https://doi.org/10.1038/onc.2013.446

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