Abstract

A unique prognostic role of the genetic duet of BRAF V600E and TERT promoter mutations in papillary thyroid cancer (PTC) has been recently established, but the role of RAS mutation in this genetic interplay remains to be established. Using The Cancer Genome Atlas (TCGA) data of patients with PTC from 19 medical centers, we investigated the interactions among the three mutations in clinical outcomes of PTC. We found that BRAF and RAS mutations were mutually exclusive, but both were associated with TERT promoter mutations, with the genetic duet of BRAF/RAS and TERT mutations occurring in 34/388 (8.76%) patients. BRAF/RAS or TERT mutation had no or minimal effect alone, whereas coexisting BRAF/RAS and TERT mutations had a robust synergistic effect on poor clinicopathologic outcomes of PTC, including disease recurrence and patient mortality. For example, PTC recurrence rate was 52% with coexisting BRAF V600E/RAS and TERT promoter mutations vs 6.9% with no mutation, corresponding to a HR of 8.17 (95% CI 3.09–21.58), which remained significant at 14.71 (95% CI 2.79–77.61) after adjustment for clinicopathologic factors and institution. BRAF/RAS mutation or TERT mutation alone minimally affected Kaplan–Meier patient survival curves, whereas the genetic duet was associated with a sharp curve decline. Thus, by confirming and expanding previous findings in single-institution studies, this multicenter data analysis establishes a six-genotype genetic prognostic model for poor outcomes of PTC with a risk order of genetic duet of BRAF V600E/RAS mutation and TERT mutation >>>>BRAF V600E = TERT mutation alone >RAS mutation alone = wild-type genes.