title: BRAF V600E and TERT promoter mutations cooperatively identify the most aggressive papillary thyroid cancer with highest recurrence.
abstract: OBJECTIVE
  To investigate the prognostic value of the BRAF V600E mutation and the recently identified TERT promoter mutation chr5:1,295,228C>T (C228T), individually and in their coexistence, in papillary thyroid cancer (PTC).
  
  
  METHODS
  We performed a retrospective study of the relationship of BRAF and TERT C228T mutations with clinicopathologic outcomes of PTC in 507 patients (365 women and 142 men) age 45.9 ± 14.0 years (mean ± SD) with a median follow-up of 24 months (interquartile range, 8 to 78 months).
  
  
  RESULTS
  Coexisting BRAF V600E and TERT C228T mutations were more commonly associated with high-risk clinicopathologic characteristics of PTC than they were individually. Tumor recurrence rates were 25.8% (50 of 194;77.60 recurrences per 1,000 person-years; 95% CI, 58.81 to 102.38) versus 9.6% (30 of 313; 22.88 recurrences per 1,000 person-years; 95% CI, 16.00 to 32.72) in BRAF mutation-positive versus -negative patients (hazard ratio [HR], 3.22; 95% CI, 2.05 to 5.07) and 47.5% (29 of 61; 108.55 recurrences per 1,000 person-years; 95% CI, 75.43 to 156.20) versus 11.4% (51 of 446; 30.21 recurrences per 1,000 person-years; 95% CI, 22.96 to 39.74) in TERT mutation-positive versus -negative patients (HR, 3.46; 95% CI, 2.19 to 5.45). Recurrence rates were 68.6% (24 of 35; 211.76 recurrences per 1,000 person-years; 95% CI, 141.94 to 315.94) versus 8.7% (25 of 287; 21.60 recurrences per 1,000 person-years; 95% CI, 14.59 to 31.97) in patients harboring both mutations versus patients harboring neither mutation (HR, 8.51; 95% CI, 4.84 to 14.97), which remained significant after clinicopathologic cofactor adjustments. Disease-free patient survival curves displayed a moderate decline with BRAF V600E or TERT C228T alone but a sharp decline with two coexisting mutations.
  
  
  CONCLUSIONS
  Coexisting BRAF V600E and TERT C228T mutations form a novel genetic background that defines PTC with the worst clinicopathologic outcomes, providing unique prognostic and therapeutic implications.
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD. mxing1@jhmi.edu.
authors.forename: Mingzhao
authors.initials: M
authors.lastname: Xing
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Rengyun
authors.initials: R
authors.lastname: Liu
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Xiaoli
authors.initials: X
authors.lastname: Liu
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Avaniyapuram Kannan
authors.initials: AK
authors.lastname: Murugan
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Guangwu
authors.initials: G
authors.lastname: Zhu
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Martha A
authors.initials: MA
authors.lastname: Zeiger
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Sara
authors.initials: S
authors.lastname: Pai
authors.affiliation: All authors: Johns Hopkins University School of Medicine, Baltimore, MD.
authors.forename: Justin
authors.initials: J
authors.lastname: Bishop
mesh_terms: D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D002291:Carcinoma, Papillary; D018572:Disease-Free Survival; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics / Q000473:pathology; D011379:Prognosis; D011401:Promoter Regions, Genetic; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics*; D012189:Retrospective Studies; D019098:Telomerase / Q000235:genetics*; D000077273:Thyroid Cancer, Papillary; D013964:Thyroid Neoplasms / Q000235:genetics* / Q000473:pathology
chemical_list: C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase