title: TERT promoter mutations and their association with BRAF V600E mutation and aggressive clinicopathological characteristics of thyroid cancer.
abstract: BACKGROUND
  Promoter mutations chr5:1,295,228C>T and chr5:1,295,250C>T (termed C228T and C250T, respectively) in the gene for telomerase reverse transcriptase (TERT) have been reported in various cancers and need to be further investigated in thyroid cancer.
  
  
  OBJECTIVE
  The aim of the study was to explore TERT promoter mutations in various thyroid tumors and examine their relationship with BRAF V600E mutation, iodine intake, and clinicopathological behaviors of thyroid cancer.
  
  
  METHODS
  TERT promoter and BRAF mutations were identified by sequencing genomic DNA of primary thyroid tumors from normal- and high-iodine regions in China, and clinicopathological correlation was analyzed.
  
  
  RESULTS
  The C228T mutation was found in 9.6% (39 of 408) of papillary thyroid cancer (PTC), C250T was found in 1.7% (7 of 408) of PTC, and they were collectively found in 11.3% (46 of 408) of PTC. C228T was found in 31.8% (7 of 22) and C250T in 4.6% (1 of 22) of follicular thyroid cancer (FTC), and they were collectively found in 36.4% (8 of 22) of FTC. No TERT mutation was found in 44 benign thyroid tumors. The two mutations occurred in 3.8% (6 of 158) of BRAF mutation-negative PTC vs 16.0% (40 of 250) of BRAF mutation-positive PTC (P = 5.87 × 10(-4)), demonstrating their association. Unlike BRAF mutation, TERT promoter mutations were not associated with high iodine intake, but they were associated with older patient age, larger tumor size, extrathyroidal invasion, and advanced stages III/IV of PTC. Coexisting TERT and BRAF mutations were even more commonly and more significantly associated with clinicopathological aggressiveness.
  
  
  CONCLUSIONS
  In this large cohort, we found TERT promoter mutations to be common, particularly in FTC and BRAF mutation-positive PTC, and associated with aggressive clinicopathological characteristics.
authors.affiliation: Laboratory for Cellular and Molecular Thyroid Research (X.L., R.L., X.S., G.Z., A.K.M., M.X.), Division of Endocrinology, Diabetes & Metabolism, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287; Department of Endocrinology & Metabolism (S.Q., C.S.), Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072, China; Department of Endocrinology & Metabolism and Institute of Endocrinology (H.G., Z.S., W.T.), The First Affiliated Hospital of China Medical University, Shenyang, Liaoning Province 110001, China; Department of Pathology (H.Y.), Changzheng Hospital, The Second Military Medical University, Shanghai 200003, China; Department of Endocrinology & Metabolism (Y.W.), The Affiliated Hospital of Medical College, Qingdao University, Qingdao, Shandong Province 266003, China; and Jilin Provincial Key Laboratory of Surgical Translational Medicine (H.S.), Department of Thyroid and Parathyroid Surgery, China-Japan Union Hospital, Jilin University, Changchun, Jilin Province 130033, China.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.forename: Shen
authors.initials: S
authors.lastname: Qu
authors.forename: Rengyun
authors.initials: R
authors.lastname: Liu
authors.forename: Chunjun
authors.initials: C
authors.lastname: Sheng
authors.forename: Xiaoguang
authors.initials: X
authors.lastname: Shi
authors.forename: Guangwu
authors.initials: G
authors.lastname: Zhu
authors.forename: Avaniyapuram Kannan
authors.initials: AK
authors.lastname: Murugan
authors.forename: Haixia
authors.initials: H
authors.lastname: Guan
authors.forename: Hongyu
authors.initials: H
authors.lastname: Yu
authors.forename: Yangang
authors.initials: Y
authors.lastname: Wang
authors.forename: Hui
authors.initials: H
authors.lastname: Sun
authors.forename: Zhongyan
authors.initials: Z
authors.lastname: Shan
authors.forename: Weiping
authors.initials: W
authors.lastname: Teng
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Xing
mesh_terms: D018263:Adenocarcinoma, Follicular / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D000328:Adult; D000368:Aged; D019943:Amino Acid Substitution; D001483:Base Sequence; D002277:Carcinoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D002291:Carcinoma, Papillary; D015331:Cohort Studies; D005260:Female; D005787:Gene Frequency; D056726:Genetic Association Studies; D018698:Glutamic Acid / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D009154:Mutation; D009361:Neoplasm Invasiveness; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology*; D014633:Valine / Q000235:genetics
chemical_list: D018698:Glutamic Acid; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase; D014633:Valine