TERT promoter mutations in melanoma survival

Abstract

Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at-risk primary melanoma patients. In this study, we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. Tumors from 300 patients with stage I/II melanoma were sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression-free and melanoma-specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease-free and melanoma-specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease-free survival was 2.3 (95% CI 1.2-4.4) and for melanoma-specific survival 5.8 (95% CI 1.9-18.3). The effect of the mutations on melanoma-specific survival in noncarriers of variant allele of the polymorphism was significant (HR 4.5, 95% CI 1.4-15.2) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.3, 95% CI 0.1-0.9). The data in this study provide preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter.

Keywords: BRAF mutations; TERT promoter mutations; disease-free survival; melanoma; melanoma-specific survival.

Figure 1.

Distribution of mutations in TERT promoter, BRAF and NRAS in primary tumors from 300 melanoma patients

Figure 2.

Kaplan-Meier analysis of differences in disease free survival (A) in melanoma patients with and without TERT promoter mutations in primary tumors; after stratification of patients into (B) non-carriers of the variant allele of the rs2853669 polymorphism (C) carriers of the variant allele; (D) in patients with and without BRAF/NRAS mutations in tumors; (E) in patients with only TERT promoter mutations, only BRAF/NRAS mutations, with both TERT promoter and BRAF/NRAS mutations and without any of those mutations in tumors. The numbers of patients at risk in each category are shown underneath at 0, 50, 100 and 150 months.

Figure 3.

Kaplan-Meier analysis of differences in melanoma-specific survival (A) in melanoma patients with and without TERT promoter mutations in primary tumors; after stratification of patients into (B) non-carriers of the variant allele of the rs2853669 polymorphism (C) carriers of the variant allele; (D) in patients with and without BRAF/NRAS mutations in tumors; (E) in patients with only TERT promoter mutations, only BRAF/NRAS mutations, with both TERT promoter and BRAF/NRAS mutations and without any of those mutations in tumors. The numbers of patients at risk in each category are shown underneath at 0, 50, 100 and 150 months.