Telomerase activation and its clinical implications in human thyroid tumors

Telomerase is a ribonucleoprotein enzyme. The catalytic and rate-limiting component of telomerase is referred to as telomerase reverse transcriptase (TERT) that plays an important role in telomere maintenance, cell immortalization and malignant transformation. Due to its aberrant expression and critical role in cancer development and progression, TERT has been suggested as a promising molecular marker for cancer diagnosis and prognosis. Thyroid cancer is the most common endocrine cancer. The diagnosis and treatment for thyroid cancer has been extensively studied; however, the molecular mechanisms underlying the roles of TERT in thyroid cancer are incompletely understood. The aim of this thesis was to explore the regulation, biological role and clinical significance of TERT in thyroid cancer.

Somatic mutations of the TERT promoter, a genetic event for telomerase activation, were first described in malignant melanoma and have then been identified in various types of cancer during the last two years. The TERT promoter mutations were detected in follicular thyroid cell- derived thyroid carcinomas but not in parafollicular C cell-derived medullary thyroid carcinoma (MTC); the presence of the mutation was associated with shorter telomeres, poor outcome and aggressive clinical features. TERT promoter mutation was also found in follicular thyroid adenoma with uncertain malignant potential, which indicates that it is an early genetic event in thyroid carcinogenesis.

Despite the absence of TERT promoter mutations, telomerase activation including TERT expression and telomerase activity was detected in more than half of MTCs, and associated with aggressive disease behavior and poor outcome. These results suggest that TERT can serve as a useful prognostic marker for MTC. It was further revealed that TERT copy number alterations, TERT promoter methylation, different TERT RNA splicing variants and other cancer-related proteins contributed to the up-regulation of TERT expression in MTC. Besides telomerase activation, alternative lengthening of telomere (ALT) was identified as another mechanism for telomere length maintenance in MTC.

The known oncogenic RET and RAS mutations were also detected in MTCs; however, no association was found between these two genetic events and clinical features. The tyrosine kinase inhibitor vandetanib decreased MTC cell viability in in vitro experiments, but proteins regulated in response to the RET pathway inhibition need to be further clarified.

In summary, this thesis provides further insights into the molecular mechanisms for telomerase activation and aberrant TERT induction, and the roles of TERT/telomerase in human thyroid carcinogenesis. More importantly, the findings underline the clinical importance of TERT/telomerase assessment in thyroid cancer.

List of scientific papers

I. Liu T, Wang N, Cao J, Sofiadis A, Dinets A, Zedenius J, Larsson C, Xu D. The age- and shorter telomere-dependent TERT promoter mutation in follicular thyroid cell-derived carcinomas. Oncogene. 2014, 33(42):4978-4984.
https://doi.org/10.1038/onc.2013.446

II. Wang N, Liu T, Sofiadis A, Juhlin CC, Zedenius J, Höög A, Larsson C, Xu D. TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA. Cancer. 2014, 120(19): 2965-2979.
https://doi.org/10.1002/cncr.28800

III. Wang N, Xu D, Sofiadis A, Höög A, Vukojevic V, Bäckdahl M, Zedenius J, Larsson C. Telomerase-dependent and independent telomere maintenance and its clinical implications in medullary thyroid carcinoma.The Journal of Clinical Endocrinology and Metabolism. 2014, 99(8), E1571-1579.
https://doi.org/10.1210/jc.2014-1158

IV. Wang N, Kjellin H, Sofiadis A, Fotouhi O, Juhlin CC, Bäckdahl M, Zedenius J, Xu D, Lehtiö J and Larsson C. Genetic background and protein expression profiles in relation to telomerase activation in medullary thyroid carcinoma. [Submitted]

V. Wang N, Kjellin H, Orre LM, Sofiadis A, Juhlin CC, Bäckdahl M, Zedenius J, Lehtiö J, Larsson C. Protein expression profiles of medullary thyroid carcinoma – relation to RET mutational status and vandetanib treatment. [Manuscript]