Abstract
Telomerase activation through the induction of its catalytic component TERT is essential in carcinogenesis. The regulatory mechanism and clinical significance underlying cancer-specific TERT expression have been extensively investigated in various human malignancies, but little is known about these in Merkel cell carcinoma (MCC), an aggressive neuroendocrine skin tumor. Here we addressed these issues by determining TERT promoter mutations, gene amplification, mRNA expression and association with clinical variables in MCC. TERT mRNA was expressed in 6/6 MCC cell lines and 41 of 43 tumors derived from 35 MCC patients. Telomerase activity was detectable in all 6 cell lines and 11 tumors analyzed. TERT promoter mutations were identified in 1/6 cell lines and 4/35 (11.4%) MCC cases. The mutation exhibited UV signature and occurred in sun-exposed areas. Increased TERT gene copy numbers were observed in 1/6 cell lines and 11/14 (79%) tumors, and highly correlated with its mRNA expression (r = 0.7419, P = 0.0024). Shorter overall survival was significantly associated with higher TERT mRNA levels in MCC patients (P = 0.032). Collectively, TERT expression and telomerase activity is widespread in MCC, and may be attributable to TERT promoter mutations and gene amplification. Higher TERT expression predicts poor patient outcomes.
Highlights
Merkel cell carcinoma (MCC), a neuroendocrine skin malignancy, is believed to originate from intraepidermal Merkel cells and predominantly occurs in the elderly population or immunocompromised individuals [1-4]
Telomerase activation and association with clinical variables were analyzed together with telomerase reverse transcriptase (TERT) expression, promoter mutation, and gene amplification using a series of 43 MCCs from 35 patients (Table 1 and Supplementary Table S1) and 6 MCC cell lines
A previous study reported detectable telomerase activity in tumor biopsies derived from 4 MCC patients [28], whereas TERT mRNA expression in MCC has not been investigated so far
Summary
Merkel cell carcinoma (MCC), a neuroendocrine skin malignancy, is believed to originate from intraepidermal Merkel cells and predominantly occurs in the elderly population or immunocompromised individuals [1-4]. We previously showed that TERT gene was frequently targeted for amplification in carcinogenesis, which contributed to telomerase activation in human malignancies [11, 12]. It has been shown that certain single nucleotide polymorphisms increase cancer risk by up-regulating TERT expression and telomerase activity [13]. Somatic TERT promoter mutations namely C228T and C250T have been identified as novel gain-of-function genetic events in up to 80% of malignant melanoma and other kinds of cancer [14-25]. All these findings, provide insights into telomerase activation in carcinogenesis, and reveal clinical significance of telomerase/TERT-related assessments in cancer diagnosis and outcome prediction. Targeting telomerase or telomere maintenance has been suggested as a novel anti-cancer strategy [26, 27]
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