title: 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.
authors.affiliation: Department of Dermatology, Instituto Valenciano De Oncologia, Valencia, Spain.
authors.forename: Eduardo
authors.initials: E
authors.lastname: Nagore
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Heidenreich
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Sívaramakrishna
authors.initials: S
authors.lastname: Rachakonda
authors.affiliation: Laboratory of Molecular Biology, Instituto Valenciano De Oncologia, Valencia, Spain.
authors.forename: Zaida
authors.initials: Z
authors.lastname: Garcia-Casado
authors.affiliation: Department of Dermatology, Instituto Valenciano De Oncologia, Valencia, Spain.
authors.forename: Celia
authors.initials: C
authors.lastname: Requena
authors.affiliation: Medical Oncology Department, Instituto Valenciano De Oncologia, Valencia, Spain.
authors.forename: Virtudes
authors.initials: V
authors.lastname: Soriano
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Frank
authors.affiliation: Department of Pathology, Instituto Valenciano De Oncologia, Valencia, Spain.
authors.forename: Victor
authors.initials: V
authors.lastname: Traves
authors.affiliation: Department of Dermatology, Hospital Arnau De Vilanova De Valencia, Valencia, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Quecedo
authors.affiliation: Department of Pathology, Hospital Arnau De Vilanova De Valencia, Valencia, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: Sanjuan-Gimenez
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.|Center for Primary Health Care Research, Lund University, Malmö, Sweden.
authors.forename: Kari
authors.initials: K
authors.lastname: Hemminki
authors.affiliation: Division of Epidemiology and Genetics, National Cancer Institute, US National Institutes of Health, Bethesda, MD.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Landi
authors.affiliation: Division of Molecular Genetic Epidemiology, German Cancer Research Center, Heidelberg, Germany.
authors.forename: Rajiv
authors.initials: R
authors.lastname: Kumar
mesh_terms: D000328:Adult; D000368:Aged; D014408:Biomarkers, Tumor / Q000235:genetics*; D018572:Disease-Free Survival; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D053208:Kaplan-Meier Estimate; D008545:Melanoma / Q000235:genetics* / Q000473:pathology; D008565:Membrane Proteins / Q000235:genetics; D008875:Middle Aged; D009367:Neoplasm Staging; D011379:Prognosis; D011401:Promoter Regions, Genetic; D016016:Proportional Hazards Models; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019098:Telomerase / Q000235:genetics*
chemical_list: D014408:Biomarkers, Tumor; D008565:Membrane Proteins; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human
keywords: BRAF mutations; TERT promoter mutations; disease-free survival; melanoma; melanoma-specific survival