title: TERT promoter mutations and gene amplification: promoting TERT expression in Merkel cell carcinoma.
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.
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska. Contributed equally to this work.
authors.forename: Hong
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Pathology, Shandong University School of Medicine, Jinan, PR China. Contributed equally to this work.
authors.forename: Tiantian
authors.initials: T
authors.lastname: Liu
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.affiliation: Department of Reconstructive Plastic Surgery, Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Viveca
authors.initials: V
authors.lastname: Björnhagen
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska.
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska.
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.affiliation: Department of Oncology-Pathology, Cancer Center Karolinska.
authors.forename: Weng-Onn
authors.initials: WO
authors.lastname: Lui
authors.affiliation: Department of Medicine-Solna, Division of Hematology and Center for Molecular Medicine. Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D015266:Carcinoma, Merkel Cell / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D005260:Female; D005784:Gene Amplification; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic; D012878:Skin Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D019098:Telomerase / Q000096:biosynthesis / Q000235:genetics*; D055815:Young Adult
chemical_list: C509186:TERT protein, human; D019098:Telomerase