Genetic Trio of BRAF and TERT Mutations and rs2853669TT in Papillary Thyroid Cancer Aggressiveness
Menée à partir du séquençage génomique de l'ADN d'échantillons tumoraux prélevés sur 608 patients atteints d'un cancer papillaire de la thyroïde (427 femmes et 181 hommes ; durée médiane de suivi : 75 mois), cette étude évalue l'intérêt de rechercher le variant rs2853669T>C pour améliorer la valeur pronostique de la mutation BRAF V600E et des mutations au niveau du promoteur du gène TERT
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.
Journal of the National Cancer Institute , résumé, 2022