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. 2014 Sep 13;106(9):dju246.
doi: 10.1093/jnci/dju246. Print 2014 Sep.

TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma

Klaus G Griewank  1 , Rajmohan Murali  2 , Joan Anton Puig-Butille  2 , Bastian Schilling  2 , Elisabeth Livingstone  2 , Miriam Potrony  2 , Cristina Carrera  2 , Tobias Schimming  2 , Inga Möller  2 , Marion Schwamborn  2 , Antje Sucker  2 , Uwe Hillen  2 , Celia Badenas  2 , Josep Malvehy  2 , Lisa Zimmer  2 , André Scherag  2 , Susana Puig  2 , Dirk Schadendorf  1
Affiliations

TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma

Klaus G Griewank et al. J Natl Cancer Inst. .

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.

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Figures

Figure 1.
Figure 1.
Associations of tumor stage at diagnosis and TERT promoter status with overall survival in 239 patients with melanomas of nonacral skin. Kaplan-Meier survival curves of overall survival according to A) tumor stage at diagnosis and B) TERT promoter status (mutant vs wild type). All statistical tests were two-sided. TERT = telomerase reverse transcriptase.
Figure 2.
Figure 2.
Recurrent mutations identified in the TERT promoter. Sanger sequencing chromatograms of representative mutations are shown. Recurrent mutations identified were found at location Chr.5:1295228C>T, Chr.5:1295228_1295229CC>TT, Chr.5:1295242_1295243CC>TT, and Chr.5:1295250C>T (according to human genome assembly hg19). A wild-type promoter sequence is shown at the top for comparison. Mutations presented in the figure are highlighted by black arrowheads and labeled applying the last three nucleotides of the first base mutated (underlined above). TERT = telomerase reverse transcriptase.
See this image and copyright information in PMC

Comment in

  • RE: TERT promoter mutation status as an independent prognostic factor in cutaneous melanoma.
    Pópulo H, Lopes JM, Sobrinho-Simões M, Soares P. Pópulo H, et al. J Natl Cancer Inst. 2015 Mar 9;107(4):djv049. doi: 10.1093/jnci/djv049. Print 2015 Apr. J Natl Cancer Inst. 2015. PMID: 25755155 No abstract available.
  • Response.
    Griewank KG, Murali R, Scherag A, Schadendorf D. Griewank KG, et al. J Natl Cancer Inst. 2015 Mar 9;107(4):djv051. doi: 10.1093/jnci/djv051. Print 2015 Apr. J Natl Cancer Inst. 2015. PMID: 25755156 No abstract available.

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