TERT MUTATIONS IN MELANOMA

TERT promoter mutations have been found to occur at high frequency in cutaneous melanoma tumor samples, exhibit a UV-signature, and lead to increased TERT gene expression. In a study reported in the Journal of the National Cancer Institute, Griewank et al found that TERT promoter mutation was independently associated with reduced survival in patients with nonacral cutaneous melanomas.

Study Details

In the study, 410 melanoma tumor samples were analyzed by Sanger sequencing for TERT promoter mutations, with mutations being identified in 154 (43%) of 362 successfully sequenced samples. Mutations were more common in melanomas with occult primary (50%) and those arising in nonacral skin (48%) and less common in mucosal (23%) and acral (19%) melanomas.

The presence of TERT promoter mutation was associated with BRAF or NRAS mutation (P < .001), histologic type (P = .002), and Breslow thickness (P < .001).

Not Predictive Overall

Overall, patients with TERT promoter mutation had a trend toward worse overall survival (median 106 vs 291 months, P = .06, vs wild-type tumors). On multivariate analysis, however, only BRAF or NRAS mutation and tumor stage at diagnosis (stage III or IV vs lower stage or increased Breslow thickness or Clark level) were independent predictors of overall survival.

Reduced Overall Survival in Nonacral Melanomas

In multivariate analysis among patients with nonacral cutaneous melanomas (69% of population), TERT promoter mutation was associated with significantly poorer overall survival (median 80 vs 291 months, hazard ratio = 2.47, P = .006, vs wild-type tumors). Other significant predictors consisted of increasing stage at diagnosis and anatomic location of primary.

The investigators concluded: “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.”

Klaus Griewank, MD, and Dirk Schadendorf, MD, of University Hospital Essen, are the corresponding authors for the Journal of the National Cancer Institute article.

The study was supported by Deutsche Forschungsgemeinschaft, Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Fondo Europeo de Desarrollo Regional, Catalan Government, European Commission under the 6th Framework Programme, U.S. National Cancer Institute, and German Federal Ministry of Education and Research. The study authors reported no potential conflicts of interest.