Adina Figl

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.

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 = .0485), and treatment choice (for the cohort with single BM-MM only) (stereotactic radiotherapy or neurosurgical metastasectomy vs others; P = .036). Cox proportional hazards models revealed pretreatment elevated level of serum LDH (hazard ratio [HR], 1.6; 95% CI, 1.3-2.0 [P = .00013]) and number of BM-MM (HR, 1.6; 95% CI, 1.3-2.0 [P = .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 = .0061]) was identified as a unique prognostic factor. CONCLUSIONS: 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.

BACKGROUND: The incidence of melanoma continues to increase in many countries, and primary prevention of melanoma includes avoidance of sunburn as well as adequate sun protection behavior. The aim of this study was to examine the prevalence of self-reported sun protection behaviors and sunburn in users of the Internet, and to identify the demographic, clinical, and attitudinal/motivational correlates of sun protection behaviors. METHODS: Self-report data were gathered on behalf of the GenoMEL consortium using an online survey available in 10 different languages, and 8,178 individuals successfully completed at least 80% of survey items, with 73% of respondents from Europe, 12% from Australia, 7% from the United States, 2% from Israel, and 6% from other countries. RESULTS: Half of all respondents and 27% of those with a previous melanoma reported at least one severe sunburn during the previous 12 months. The strongest factors associated with sun protection behavior were perceived barriers to protection (beta = -0.44/beta = -0.37), and respondents who reported a positive attitude toward suntans were less likely to protect (beta = -0.16/beta = -0.14). Reported use of protective clothing and shade, as well as avoidance of midday sun exposure, were more strongly related to reduced risk of sunburn than sunscreen use. CONCLUSIONS: Despite widespread dissemination of public health messages about the importance of sun protection, a substantial proportion of this international sample, including respondents with a previous melanoma, reported inadequate sun protection behaviors resulting in severe sunburn. IMPACT: Future strategies to decrease sunburn should target the practical, social, and psychological barriers associated with nonuptake of sun protection.

The aim of this study was to analyse whether altered cytokine production by cord blood (CB) T cells is of relevance regarding the development of allergic diseases during the first 2 yr of life independent from known or suspected risk factors for allergy. Within an ongoing birth cohort study (Life style - Immune System - Allergy; LISA) the cytokine production of PMA/ionomycin-stimulated CB cells was measured by intracellular cytokine staining. Data of 98 children from Leipzig and Munich with complete information on cytokine production at birth and allergic outcomes during the first 2 yr were analysed. Statistical analysis was performed using a regression model adjusted for gender, month of birth, parental history of atopy, parental education, exposure to environmental tobacco smoke, maternal smoking during pregnancy, renovation activities during pregnancy, pet ownership and study centre. During the first 2 yr of life, 17.3% of the children developed a physician-diagnosed atopic dermatitis. Children with reduced frequencies of interferon-gamma (IFN-gamma)-producing CD4(+) T cells in the CB (1st quartile) had a higher risk to develop atopic dermatitis (adjusted OR 5.16, 95% CI: 1.04-25.6). Furthermore, a high percentage of interleukin (IL)-4-producing T cells in CB in children from the Leipzig cohort were associated with an increased risk for atopic dermatitis (adjusted OR 8.92, 95% CI: 1.40-56.93 for the 90th percentile). CD8(+) cytokine-producing CB T cells had no relation to increased risk for atopic dermatitis. Low amounts of IFN-gamma and high amounts of IL-4-producing T cells at birth may enhance the risk of subsequent development of atopic dermatitis.

Variation within the melanocortin receptor 1 (MC1R) gene, that influences phenotypic traits and susceptibility to melanoma, is abundant across the populations. We assessed and compared the risk of melanoma in 2 European populations, German and Spanish, by genotyping MC1R variants through direct DNA sequencing from 1,185 melanoma cases and 1,582 controls. The presence of any variant in both populations was associated with a significantly increased risk of melanoma (odds ratio OR = 1.67, 95% confidence interval CI 1.40-1.99). The population attributable fractions (PAF) associated with the MC1R variants in both populations was over 25%. However, the results showed a statistically significant (p < 0.0001) higher frequency of MC1R variants in the German (70%) than in the Spanish population (60%). The red-hair colour (RHC) variants, though associated with increased risk in both populations, were more common in the German than in the Spanish population (p < 0.0001). Interestingly, non-RHC variants increased the disease risk in the Spanish (OR = 1.60, 95% CI 1.20-2.14) but not in the German population (OR = 1.07, 95% CI 0.80-1.44). Although RHC variants explained a major proportion of the observed PAF in the German population, in the Spanish population the major contributor to the PAF was the non-RHC V60L variant. We also observed reduced historic linkage disequilibrium between the variants V92M and T314T in the gene in German melanoma cases. In conclusion, our data underscored the unambiguous importance of the MC1R variants towards the population burden of melanoma. However, the variants that are associated with the disease differ between the investigated populations.