title: Association of TERT Promoter Mutation, But Not BRAF Mutation, With Increased Mortality in PTC.
abstract: BACKGROUND
  Papillary thyroid carcinoma (PTC) carrying the BRAF mutation has been reported to be associated with high recurrence and potentially increased mortality. PTC carrying the TERT promoter mutation has been associated with older age, recurrence, and aggressive disease.
  
  
  OBJECTIVE
  The objective of this study was to determine the association of BRAF and TERT promoter gene alterations with recurrence and survival in a high-risk population.
  
  
  METHODS
  Genomic DNA was analyzed for the BRAF mutation from 256 persistent/recurrent PTC (p/rPTC; 202 new, 54 previously reported) and for the TERT promoter mutation and polymorphism (242 p/rPTC). Two-tailed Fisher exact tests or the Pearson χ(2) test were performed for the associations between mutations and other variables. Overall and disease-free survivals were compared by log rank tests on Kaplan-Meier plots and by Cox regression analysis. TERT promoter constructs were tested in PTC cell lines to determine their activities in these cells.
  
  
  RESULTS
  BRAF V600E mutation was identified in 235 of 256 (91.8%), TERT promoter mutation at -124 was detected in 77 of 242 (31.8%), and TERT promoter polymorphism at -245 was found in 113 of 242 (46.7%) p/rPTC patients. A significant difference in survival was found in p/rPTC patients with the TERT promoter mutation, which also displayed increased activity in vitro as compared to the nonmutated promoter sequence. No association was noted between the BRAF mutation or TERT promoter polymorphism and recurrence or survival. A drawback of our study could be the limited number of patients with nonmutated BRAF (21 of 256 [8.2%]).
  
  
  CONCLUSIONS
  Mutation in the TERT promoter, but not in BRAF, was associated with decreased survival in 19 (24.7%) p/rPTC patients who died of disease and in 38 (49.4%) p/rPTC patients who died at last contact. The presence or absence of the BRAF mutation and TERT promoter polymorphism, however, was not significantly correlated with survival.
authors.affiliation: Head and Neck Surgical Oncology and Head and Neck Endocrine Surgery (J.R.G), University of California, San Francisco Medical Center, San Francisco, California 94143; and Departments of Head and Neck Surgery (Y.C.H., D.B.R., H.H., S.Y.L., G.L.C.), Pathology (M.D.W), Molecular and Cellular Oncology (S.Y.L.), and Cancer Biology (G.L.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: George
authors.affiliation: Head and Neck Surgical Oncology and Head and Neck Endocrine Surgery (J.R.G), University of California, San Francisco Medical Center, San Francisco, California 94143; and Departments of Head and Neck Surgery (Y.C.H., D.B.R., H.H., S.Y.L., G.L.C.), Pathology (M.D.W), Molecular and Cellular Oncology (S.Y.L.), and Cancer Biology (G.L.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Ying C
authors.initials: YC
authors.lastname: Henderson
authors.affiliation: Head and Neck Surgical Oncology and Head and Neck Endocrine Surgery (J.R.G), University of California, San Francisco Medical Center, San Francisco, California 94143; and Departments of Head and Neck Surgery (Y.C.H., D.B.R., H.H., S.Y.L., G.L.C.), Pathology (M.D.W), Molecular and Cellular Oncology (S.Y.L.), and Cancer Biology (G.L.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Williams
authors.affiliation: Head and Neck Surgical Oncology and Head and Neck Endocrine Surgery (J.R.G), University of California, San Francisco Medical Center, San Francisco, California 94143; and Departments of Head and Neck Surgery (Y.C.H., D.B.R., H.H., S.Y.L., G.L.C.), Pathology (M.D.W), Molecular and Cellular Oncology (S.Y.L.), and Cancer Biology (G.L.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Dianna B
authors.initials: DB
authors.lastname: Roberts
authors.affiliation: Head and Neck Surgical Oncology and Head and Neck Endocrine Surgery (J.R.G), University of California, San Francisco Medical Center, San Francisco, California 94143; and Departments of Head and Neck Surgery (Y.C.H., D.B.R., H.H., S.Y.L., G.L.C.), Pathology (M.D.W), Molecular and Cellular Oncology (S.Y.L.), and Cancer Biology (G.L.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Hu
authors.initials: H
authors.lastname: Hei
authors.affiliation: Head and Neck Surgical Oncology and Head and Neck Endocrine Surgery (J.R.G), University of California, San Francisco Medical Center, San Francisco, California 94143; and Departments of Head and Neck Surgery (Y.C.H., D.B.R., H.H., S.Y.L., G.L.C.), Pathology (M.D.W), Molecular and Cellular Oncology (S.Y.L.), and Cancer Biology (G.L.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Stephen Y
authors.initials: SY
authors.lastname: Lai
authors.affiliation: Head and Neck Surgical Oncology and Head and Neck Endocrine Surgery (J.R.G), University of California, San Francisco Medical Center, San Francisco, California 94143; and Departments of Head and Neck Surgery (Y.C.H., D.B.R., H.H., S.Y.L., G.L.C.), Pathology (M.D.W), Molecular and Cellular Oncology (S.Y.L.), and Cancer Biology (G.L.C.), The University of Texas MD Anderson Cancer Center, Houston, Texas 77030.
authors.forename: Gary L
authors.initials: GL
authors.lastname: Clayman
mesh_terms: D000328:Adult; D000367:Age Factors; D002277:Carcinoma / Q000235:genetics* / Q000401:mortality*; D002291:Carcinoma, Papillary; D004252:DNA Mutational Analysis; D018450:Disease Progression; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation / Q000235:genetics; D011110:Polymorphism, Genetic / Q000235:genetics; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012008:Recurrence; D016019:Survival Analysis; D019098:Telomerase / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000401:mortality*
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase