title: Highly prevalent TERT promoter mutations in aggressive thyroid cancers.
abstract: Mutations 1 295 228 C>T and 1 295 250 C>T (termed C228T and C250T respectively), corresponding to -124 C>T and -146 C>T from the translation start site in the promoter of the telomerase reverse transcriptase (TERT) gene, have recently been reported in human cancers, but not in thyroid cancers yet. We explored these mutations in thyroid cancers by genomic sequencing of a large number of primary tumor samples. We found the C228T mutation in 0 of 85 (0.0%) benign thyroid tumors, 30 of 257 (11.7%) papillary thyroid cancers (PTC), 9 of 79 (11.4%) follicular thyroid cancers (FTC), 3 of 8 (37.5%) poorly differentiated thyroid cancers (PDTC), 23 of 54 (42.6%) anaplastic thyroid cancers (ATC), and 8 of 12 (66.7%) thyroid cancer cell lines. The C250T mutation was uncommon, but mutually exclusive with the C228T mutation, and the two mutations were collectively found in 11 of 79 (13.9%) FTC, 25 of 54 (46.3%) ATC, and 11 of 12 (91.7%) thyroid cancer cell lines. Among PTC variants, the C228T mutation was found in 4 of 13 (30.8%) tall-cell PTC (TCPTC), 23 of 187 (12.3%) conventional PTC, and 2 of 56 (3.6%) follicular variant PTC samples. No TERT mutation was found in 16 medullary thyroid cancer samples. The C228T mutation was associated with the BRAF V600E mutation in PTC, being present in 19 of 104 (18.3%) BRAF mutation-positive PTC vs 11 of 153 (7.2%) the BRAF mutation-negative PTC samples (P=0.0094). Conversely, BRAF mutation was found in 19 of 30 (63.3%) C228T mutation-positive PTC vs 85 of 227 (37.4%) C228T mutation-negative PTC samples (P=0.0094). We thus for the first time, to our knowledge, demonstrate TERT promoter mutations in thyroid cancers, that are particularly prevalent in the aggressive thyroid cancers TCPTC, PDTC, ATC and BRAF mutation-positive PTC, revealing a novel genetic background for thyroid cancers.
authors.affiliation: Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology and Metabolism, Johns Hopkins University School of Medicine, 1830 East Monument Street, Baltimore, MD 21287, USA.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Justin
authors.initials: J
authors.lastname: Bishop
authors.forename: Yuan
authors.initials: Y
authors.lastname: Shan
authors.forename: Sara
authors.initials: S
authors.lastname: Pai
authors.forename: Dingxie
authors.initials: D
authors.lastname: Liu
authors.forename: Avaniyapuram Kannan
authors.initials: AK
authors.lastname: Murugan
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Adel K
authors.initials: AK
authors.lastname: El-Naggar
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Xing
mesh_terms: D045744:Cell Line, Tumor; D006801:Humans; D009154:Mutation; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019098:Telomerase / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase
keywords: BRAF V600E mutation; TERT promoter mutations; telomerase reverse transcriptase; thyroid cancers; thyroid tumorigenesis