Klaus G Griewank1, Rajmohan Murali2, Joan Anton Puig-Butille2, Bastian Schilling2, Elisabeth Livingstone2, Miriam Potrony2, Cristina Carrera2, Tobias Schimming2, Inga Möller2, Marion Schwamborn2, Antje Sucker2, Uwe Hillen2, Celia Badenas2, Josep Malvehy2, Lisa Zimmer2, André Scherag2, Susana Puig2, Dirk Schadendorf1. 1. Department of Dermatology,University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen and the German Cancer Consortium (KGG, BS, EL, TS, IM, MS, AS, UH, LZ, DS), Germany; Department of Pathology and Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY (RM); CIBER Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain (JAPB, MP, CC, CB, JM, SP); Department of Dermatology, Hospital Clinic Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain (CC, JM, SP); Biochemistry and Molecular Genetics Department, Hospital Clinic Barcelona, IDIBAPS, Barcelona, Spain (CB); Integriertes Forschungs- und Behandlungszentrum (IFB) Sepsis und Sepsisfolgen Center for Sepsis Control and Care (CSCC) University Hospital Jena, Jena, Germany (AS). klaus.griewank@uk-essen.de dirk.schadendorf@uk-essen.de. 2. Department of Dermatology,University Hospital Essen, West German Cancer Center, University Duisburg-Essen, Essen and the German Cancer Consortium (KGG, BS, EL, TS, IM, MS, AS, UH, LZ, DS), Germany; Department of Pathology and Marie-Josée and Henry R. Kravis Center for Molecular Oncology, Memorial Sloan Kettering Cancer Center, New York, NY (RM); CIBER Enfermedades Raras, Instituto de Salud Carlos III, Barcelona, Spain (JAPB, MP, CC, CB, JM, SP); Department of Dermatology, Hospital Clinic Barcelona, IDIBAPS, Universitat de Barcelona, Barcelona, Spain (CC, JM, SP); Biochemistry and Molecular Genetics Department, Hospital Clinic Barcelona, IDIBAPS, Barcelona, Spain (CB); Integriertes Forschungs- und Behandlungszentrum (IFB) Sepsis und Sepsisfolgen Center for Sepsis Control and Care (CSCC) University Hospital Jena, Jena, Germany (AS).
Abstract
BACKGROUND: Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanoma patients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. METHODS: 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. RESULTS: TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). CONCLUSIONS: UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis.
BACKGROUND: Recently, TERT promoter mutations were identified at high frequencies in cutaneous melanoma tumor samples and cell lines. The mutations were found to have a UV-signature and to lead to increased TERT gene expression. We analyzed a large cohort of melanomapatients for the presence and distribution of TERT promoter mutations and their association with clinico-pathological characteristics. METHODS: 410 melanoma tumor samples were analyzed by Sanger sequencing for the presence of TERT promoter mutations. An analysis of associations between mutation status and various clinical and pathologic variables was performed. RESULTS:TERT promoter mutations were identified in 154 (43%) of 362 successfully sequenced melanomas. Mutation frequencies varied between melanoma subtype, being most frequent in melanomas arising in nonacral skin (48%) and melanomas with occult primary (50%), and less frequent in mucosal (23%), and acral (19%) melanomas. Mutations carried a UV signature (C>T or CC>TT). The presence of TERT promoter mutations was associated with factors such as BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001). TERT promoter mutation was independently associated with poorer overall survival in patients with nonacral cutaneous melanomas (median survival 80 months vs 291 months for wild-type; hazard ratio corrected for other covariates 2.47; 95% confidence interval [CI] = 1.29 to 4.74; P = .006). CONCLUSIONS: UV-induced TERT promoter mutations are one of the most frequent genetic alterations in melanoma, with frequencies varying depending on melanoma subtype. In nonacral cutaneous melanomas, presence of TERT promoter mutations is independently associated with poor prognosis.
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