title: TERT promoter mutation as an early genetic event activating telomerase in follicular thyroid adenoma (FTA) and atypical FTA.
abstract: BACKGROUND
  The telomerase reverse transcriptase (TERT) promoter mutations C228T and C250T have been found in many malignancies, including in thyroid carcinomas. However, it is unclear how early these mutations occur in thyroid tumorigenesis.
  
  
  METHODS
  The study included primary tumors from 58 patients initially diagnosed with follicular thyroid adenoma (FTA), a benign entity, 18 with atypical FTA (AFTA) having an uncertain malignant potential, and 52 with follicular thyroid carcinoma (FTC). Sanger sequencing was used to investigate the mutational status of the TERT promoter. Telomere length and TERT messenger RNA (mRNA) expression were determined using quantitative polymerase chain reaction (PCR). Telomerase activity was assessed using a Telomerase PCR enzyme-linked immunosorbent assay kit.
  
  
  RESULTS
  The C228T mutation was identified in 1 of 58 FTA (2%) and 3 of 18 AFTA (17%) samples. These 4 tumors all expressed TERT mRNA and telomerase activity, whereas the majority of C228T-negative adenomas lacked TERT expression (C228T versus wild-type, P = .008). The C228T mutation was associated with NRAS gene mutations (P = .016). The patient with C228T-mutated FTA later developed a scar recurrence and died of FTC, whereas none of the remaining 57 patients with FTA had recurrence. No recurrence occurred in 3 patients with AFTA who carried C228T during the follow-up period (36-285 months). Nine of the 52 FTCs (17%) exhibited the TERT mutation (8 of 9 C228T and 1 of 9 C250T), and the presence of the mutation was associated with shorter patient survival.
  
  
  CONCLUSIONS
  TERT promoter mutations may occur as an early genetic event in thyroid follicular tumors that have not developed malignant features on routine histopathological workup.
authors.affiliation: Department of Oncology-Pathology and Cancer Center Karolinska, Karolinska Institutet and Karolinska University Hospital Solna, Stockholm, Sweden.
authors.forename: Na
authors.initials: N
authors.lastname: Wang
authors.forename: Tiantian
authors.initials: T
authors.lastname: Liu
authors.forename: Anastasios
authors.initials: A
authors.lastname: Sofiadis
authors.forename: C Christofer
authors.initials: CC
authors.lastname: Juhlin
authors.forename: Jan
authors.initials: J
authors.lastname: Zedenius
authors.forename: Anders
authors.initials: A
authors.lastname: Höög
authors.forename: Catharina
authors.initials: C
authors.lastname: Larsson
authors.forename: Dawei
authors.initials: D
authors.lastname: Xu
mesh_terms: D000236:Adenoma / Q000201:enzymology* / Q000235:genetics*; D000328:Adult; D000368:Aged; D003545:Cysteine; D004789:Enzyme Activation; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009154:Mutation; D011401:Promoter Regions, Genetic / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D019098:Telomerase / Q000235:genetics / Q000378:metabolism*; D013912:Threonine; D013964:Thyroid Neoplasms / Q000201:enzymology* / Q000235:genetics*
chemical_list: D008565:Membrane Proteins; D013912:Threonine; C509186:TERT protein, human; D019098:Telomerase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human; D003545:Cysteine
keywords: TERT promoter mutation; atypical follicular thyroid adenoma; benign entity; follicular thyroid adenoma; follicular thyroid carcinoma; telomerase