Genetic Trio of BRAF and TERT Mutations and rs2853669TT in Papillary Thyroid Cancer Aggressiveness

Abstract

Background BRAF V600E and TERT promoter mutations are core components in current genetic-based risk assessment for precision management of papillary thyroid cancer (PTC). It remains unknown whether this could be refined to even better precision by a widely recognized prognostic single nucleotide polymorphism (SNP), rs2853669T>C, in the TERT promoter. Methods Genetic status of mutations and SNP were examined by sequencing genomic DNA from PTC in 608 patients (427 women and 181 men) aged 47 years (IQR 37-57), with a median follow-up time of 75 months (IQR 36 to 123), and their relationship with clinical outcomes was analyzed. Luciferase reporter assay was performed to examine TERT promoter activities. Results TERT promoter mutations showed a strong association with PTC recurrence in the presence of genotype TT of rs2853669 (adjusted HR = 2.12, 95% CI 1.10-4.12) but not TC/CC (adjusted HR = 1.17, 95% CI 0.56-2.41). TERT and BRAF mutations commonly coexisted and synergistically promoted PTC recurrence. With this genetic duet, TT of rs2853669 showed a robustly higher disease recurrence compared with TC/CC (adjusted HR = 14.26, 95% CI 2.86-71.25). Patients with the genetic trio of BRAF V600E, TERT mutation and TT of rs2853669 had a recurrence of 76.5% vs recurrence of 8.4% with neither mutation and with TC/CC (HR = 13.48, 95% CI 6.44-28.21). T allele of rs2853669 strongly increased TERT promoter, particularly the mutant promoter. Conclusions SNP rs2853669T>C dramatically refines the prognostic power of BRAF V600E and TERT promoter mutations to a higher precision, suggesting the need for including this SNP in the current genetic-based risk prognostication of PTC.