title: Prognostic effects of TERT promoter mutations are enhanced by coexistence with BRAF or RAS mutations and strengthen the risk prediction by the ATA or TNM staging system in differentiated thyroid cancer patients.
abstract: Recent reports suggest that mutations in the promoter of the gene encoding telomerase reverse transcriptase (TERT) affect thyroid cancer outcomes.
  
  
  
  In all, 551 patients with differentiated thyroid cancer (DTC) enrolled in this study. The median follow-up duration was 4.8 years (interquartile range, 3.4-10.6 years).
  
  
  
  TERT promoter mutations were detected in 25 DTCs (4.5%): 2.8% in neither BRAF-mutated nor RAS-mutated tumors, 4.8% in BRAF-mutated tumors, and 11.3% in RAS-mutated tumors. Moreover, they were frequently observed in American Thyroid Association (ATA) high-risk and TNM stage III/IV groups (9.1% and 12.9%, respectively). The coexistence of BRAF or RAS with TERT promoter mutations increased aggressive clinicopathologic features, recurrence (hazard ratio [HR] for BRAF, 4.64; 95% confidence interval [CI], 1.42-15.18; HR for RAS, 5.36; 95% CI, 1.20-24.02), and mortality (HR for BRAF, 15.13; 95% CI, 1.55-148.23; HR for RAS, 14.75; 95% CI, 1.30-167.00), even after adjustments for the age at diagnosis and sex, although the significance was lost after additional adjustments for pathologic characteristics. Furthermore, TERT promoter mutations significantly increased the risk of both recurrence and mortality in the ATA high-risk (HR for recurrence, 5.79; 95% CI, 2.07-16.18; HR for mortality, 16.16; 95% CI, 2.10-124.15) and TNM stage III/IV groups (HR for recurrence, 3.60; 95% CI, 1.19-10.85; HR for mortality, 9.06; 95% CI, 2.09-39.26).
  
  
  
  The coexistence of BRAF or RAS mutations enhanced the prognostic effects of TERT promoter mutations. Furthermore, TERT promoter mutations strengthened the predictions of mortality and recurrence by the ATA and TNM staging systems, particularly for high-risk patients with DTC. Cancer 2016;122:1370-1379. © 2016 American Cancer Society.
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Young Shin
authors.initials: YS
authors.lastname: Song
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.|Department of Internal Medicine, National Medical Center, Seoul, Korea.
authors.forename: Jung Ah
authors.initials: JA
authors.lastname: Lim
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.|Department of Internal Medicine, Kangwon National University Hospital, Chuncheon, Korea.
authors.forename: Hoonsung
authors.initials: H
authors.lastname: Choi
authors.affiliation: Department of Pathology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jae-Kyung
authors.initials: JK
authors.lastname: Won
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.|Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Jae Hoon
authors.initials: JH
authors.lastname: Moon
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Sun Wook
authors.initials: SW
authors.lastname: Cho
authors.affiliation: Department of Surgery, Seoul National University College of Medicine, Seoul, Korea.|Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.
authors.forename: Kyu Eun
authors.initials: KE
authors.lastname: Lee
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.|Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.
authors.forename: Young Joo
authors.initials: YJ
authors.lastname: Park
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.|Department of Internal Medicine, Boramae Medical Center, Seoul, Korea.
authors.forename: Ka Hee
authors.initials: KH
authors.lastname: Yi
authors.affiliation: Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Do Joon
authors.initials: DJ
authors.lastname: Park
authors.affiliation: Genomic Medicine Institute, Medical Research Center, Seoul National University, Seoul, Korea.|Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
authors.forename: Jeong-Sun
authors.initials: JS
authors.lastname: Seo
mesh_terms: D000328:Adult; D005260:Female; D005500:Follow-Up Studies; D011905:Genes, ras; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D009367:Neoplasm Staging; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D019098:Telomerase / Q000235:genetics*; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D013997:Time Factors
chemical_list: D048493:Proto-Oncogene Proteins B-raf; D019098:Telomerase
keywords: differentiated thyroid cancer; mortality; prognosis; recurrence; telomerase reverse transcriptase (TERT) promoter mutations