When Somatic Mutations Are Associated With a Higher Aggressive Behavior—A Story of Announced Evidence—Reply

In Reply We appreciate the enthusiastic comments of Rossi et al on our study¹ concerning prognostic BRAF V600E and TERT promoter mutations in papillary thyroid cancer (PTC). We agree with all their views. In our initial study reporting TERT promoter mutations in thyroid cancer, we observed an interesting coexistence of BRAF V600E and TERT promoter mutations in PTC,² which has now been widely confirmed.³ We hypothesized that this oncogene duet likely represented a genetic background evolutionally selected with a superior survival advantage, which could translate into poor tumor behaviors.^1-5 This was first supported by our finding that BRAF V600E and TERT promoter mutations had a robust synergistic effect on the recurrence and aggressive pathological behaviors of PTC.⁴ This is now also supported by a strong synergistic effect of the 2 mutations on PTC-related mortality.¹ In addition to the reasons suggested by Rossi et al, these results provide an explanation for the inconsistent results on the prognostic value of BRAF mutation in previous studies: because TERT promoter mutation is relatively uncommon in PTC, depending on the prevalence of TERT promoter mutations and hence the prevalence of its duet with BRAF V600E, the apparent association of clinical outcomes with the overall BRAF V600E may vary in different studies. Rossi et al appreciate our 4-genotype model for mortality risk.¹ Its essence is that BRAF V600E and TERT promoter mutation each alone is associated with a modest risk while the genetic duet is associated with a sharply increased risk, and virtually no PTC-related death occurs in patients harboring neither mutation.¹