Cutaneous melanoma occurs in both familial and sporadic forms. We investigated a melanoma-prone family through linkage analysis and high-throughput sequencing and identified a disease-segregating germline mutation in the promoter of the telomerase reverse transcriptase (TERT) gene, which encodes the catalytic subunit of telomerase. The mutation creates a new binding motif for Ets transcription factors and ternary complex factors (TCFs) near the transcription start and, in reporter gene assays, caused up to twofold increase in transcription. We then screened the TERT promoter in sporadic melanoma and observed recurrent ultraviolet signature somatic mutations in 125 of 168 (74%) of human cell lines derived from metastatic melanomas, 45 of 53 corresponding metastatic tumor tissues (85%), and 25 of 77 (33%) primary melanomas. The majority of those mutations occurred at two positions in the TERT promoter and also generated binding motifs for Ets/TCF transcription factors.

; on behalf of the Dermatologic Cooperative Oncology Group and the National Interdisciplinary Working Group on Melanoma BACKGROUND: This multicenter study aimed to identify prognostic factors in patients with brain metastases from malignant melanoma (BM-MM). METHODS: In a retrospective survey in 9 cancer centers of the German Cancer Society, 692 patients were identified with BM-MM during the period 1986 through 2007. Overall survival was analyzed using a Kaplan-Meier estimator and compared with log-rank analysis. Cox proportional hazards models were used to identify prognostic factors significant for survival. RESULTS: The median overall survival of the entire cohort was 5.0 months (95% confidence interval [95% CI], 4 months-5 months). Significant prognostic factors in the univariate Kaplan-Meier analysis were Karnofsky performance status (70% vs <70%; P < .001), number of BM-MM (single vs multiple; P < .001), pretreatment levels of lactate dehydrogenase (LDH) (normal vs elevated; P < .001) and S-100 (normal vs elevated; P < .001), prognostic groups according to Radiation Therapy Oncology Group (class I vs class II vs class III; P ¼ .0485), and treatment choice (for the cohort with single BM-MM only) (stereotactic radiotherapy or neurosurgical metastasectomy vs others; P ¼ .036). Cox proportional hazards models revealed pretreatment elevated level of serum LDH (hazard ratio [HR], 1.6; 95% CI, 1.3-2.0 [P ¼ .00013]) and number of BM-MM (HR, 1.6; 95% CI, 1.3-2.0 [P ¼ .00011]) to be independent prognostic variables in the entire cohort, whereas in patients with a single BM-MM, treatment choice (HR, 1.5; 95% CI, 1.1-1.9 [P ¼ .0061]) was identified as a unique prognostic factor. CONCLU-SIONS: The overall survival of patients with BM-MM primarily depends on the number of metastases and pretreatment level of LDH. In the case of a single brain metastasis, stereotactic radiotherapy or neurosurgical metastasectomy is by far the most important factor for improving survival.