title: Mortality Risk Stratification by Combining BRAF V600E and TERT Promoter Mutations in Papillary Thyroid Cancer: Genetic Duet of BRAF and TERT Promoter Mutations in Thyroid Cancer Mortality.
abstract: OBJECTIVE
  BRAF V600E and TERT promoter mutations can coexist in papillary thyroid cancer (PTC). This genetic duet was indicated to be involved in the aggressiveness of PTC, but its prognostic value in PTC-related mortality remains to be specifically established.
  
  
  OBJECTIVE
  To establish the prognostic power of this genetic duet in PTC-specific mortality.
  
  
  METHODS
  This genetic-clinical correlation study examined BRAF V600E and TERT promoter mutations (chr5:1,295,228C>T and chr5:1,295,250C>T) and PTC-specific mortality in 1051 patients (764 women and 287 men) with a median (interquartile range [IQR]) age of 46 (36-57) years, with a median (IQR) follow-up time of 89 (48-142) months (7.4 years).
  
  
  METHODS
  BRAF V600E and TERT promoter mutation patterns and associated patient deaths caused by PTC.
  
  
  RESULTS
  Papillary thyroid cancer-specific mortality occurred in 4 of 629 patients (0.6%) with neither mutation; 7 of 292 (2.4%) with BRAF V600E alone; 4 of 64 (6.3%) with TERT promoter mutation alone; and 15 of 66 (22.7%) with the genetic duet; and deaths per 1000-person years in patients harboring neither mutation, BRAF V600E alone, TERT mutation alone, or both mutations were 0.80 (95% CI, 0.30-2.13), 3.08 (95% CI, 1.47-6.46), 6.62 (95% CI, 2.48-17.64), and 29.86 (95% CI, 18.00-49.52), respectively. Compared with patients harboring neither mutation, HRs (95% CIs) for PTC-specific mortality were 3.08 (0.87-10.84) for BRAF V600E alone; 8.18 (2.04-32.75) with TERT mutation alone; and 37.77 (12.50-114.09) with both mutations. Papillary thyroid cancer-specific mortality for cases with both mutations remained significant (HR, 9.34; 95% CI, 2.53-34.48) after adjustment for clinicopathological factors, and the genetic duet showed a strong incremental and synergistic impact over either mutation alone. Kaplan-Meier analyses revealed a flat PTC-specific patient survival curve with neither mutation, a modest decline in the curve with either mutation alone, and a sharp decline in the curve with coexisting mutations. Even more robust mortality associations of the genetic duet were seen when only conventional-variant PTC (CPTC) was analyzed (HR, 54.46; 95% CI, 12.26-241.82), which remained strongly significant (HR, 18.56; 95% CI, 2.97-116.18) after adjustment for clinicopathological factors.
  
  
  CONCLUSIONS
  These results demonstrate a simple 4-genotype classification of PTC, particularly CPTC, with a disease-specific mortality risk order of the genetic duet>>>>BRAF V600E alone = TERT promoter mutation alone > wild-type for both genes, representing a powerful molecular prognostic system that can help pinpoint patients with the highest mortality risk.
authors: Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Rengyun
authors: R
authors: Liu
authors: Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Justin
authors: J
authors: Bishop
authors: Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Guangwu
authors: G
authors: Zhu
authors: Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Tao
authors: T
authors: Zhang
authors: Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Paul W
authors: PW
authors: Ladenson
authors: Laboratory for Cellular and Molecular Thyroid Research, Division of Endocrinology, Diabetes, & Metabolism, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland.
authors: Mingzhao
authors: M
authors: Xing