Publications by authors named "Adina Figl"

12 Publications

  • Page 1 of 1

TERT promoter mutations in familial and sporadic melanoma.

Science 2013 Feb 24;339(6122):959-61. Epub 2013 Jan 24.

Division of Molecular Genetic Epidemiology, German Cancer Research Center, Im Neuenheimer Feld 580, 69120 Heidelberg, Germany.

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.
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http://dx.doi.org/10.1126/science.1230062DOI Listing
February 2013

Skin examination behavior: the role of melanoma history, skin type, psychosocial factors, and region of residence in determining clinical and self-conducted skin examination.

Arch Dermatol 2012 Oct;148(10):1142-51

School of Women’s and Children’s Health, Faculty of Medicine, University of New South Wales, Kensington, NSW, Australia.

Objective: To examine the frequency and correlates of skin examination behaviors in an international sample of individuals at varying risk of developing melanoma.

Design: A cross-sectional, web-based survey.

Setting: Data were collected from the general population over a 20-month period on behalf of the Melanoma Genetics Consortium (GenoMEL).

Participants: A total of 8178 adults from Northern (32%), Central (33%), and Southern (14%) Europe, Australia (13%), and the United States (8%).

Main Outcome Measures: Self-reported frequency of skin self-examination (SSE) and clinical skin examination (CSE).

Results: After adjustment for age and sex, frequency of skin examination was higher in both Australia (odds ratio [OR]SSE=1.80 [99% CI, 1.49-2.18]; ORCSE=2.68 [99% CI, 2.23-3.23]) and the United States (ORSSE=2.28 [99% CI, 1.76-2.94]; ORCSE=3.39 [99% CI, 2.60-4.18]) than in the 3 European regions combined. Within Europe, participants from Southern Europe reported higher rates of SSE than those in Northern Europe (ORSSE=1.61 [99% CI, 1.31-1.97]), and frequency of CSE was higher in both Central (ORCSE=1.47 [99% CI, 1.22-1.78]) and Southern Europe (ORCSE=3.46 [99% CI, 2.78, 4.31]) than in Northern Europe. Skin examination behavior also varied according to melanoma history: participants with no history of melanoma reported the lowest levels of skin examination, while participants with a previous melanoma diagnosis reported the highest levels. After adjustment for region, and taking into account the role of age, sex, skin type, and mole count, engagement in SSE and CSE was associated with a range of psychosocial factors, including perceived risk of developing melanoma; perceived benefits of, and barriers to, skin examination; perceived confidence in one's ability to engage in screening; and social norms. In addition, among those with no history of melanoma, higher cancer-related worry was associated with greater frequency of SSE.

Conclusions: Given the strong association between psychosocial factors and skin examination behaviors, particularly among people with no history of melanoma, we recommend that greater attempts be made to integrate psycho-education into the fabric of public health initiatives and clinical care, with clinicians, researchers, and advocacy groups playing a key role in guiding individuals to appropriate tools and resources.
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http://dx.doi.org/10.1001/archdermatol.2012.1817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4965805PMC
October 2012

Number of metastases, serum lactate dehydrogenase level, and type of treatment are prognostic factors in patients with brain metastases of malignant melanoma.

Cancer 2011 Apr 8;117(8):1697-703. Epub 2010 Nov 8.

Division of Dermatooncology, Department of Dermatology, University Hospital Tuebingen, Tuebingen, Germany.

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.
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http://dx.doi.org/10.1002/cncr.25631DOI Listing
April 2011

Predictors of sun protection behaviors and severe sunburn in an international online study.

Cancer Epidemiol Biomarkers Prev 2010 Sep 19;19(9):2199-210. Epub 2010 Jul 19.

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

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.
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http://dx.doi.org/10.1158/1055-9965.EPI-10-0196DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672402PMC
September 2010

Single-nucleotide polymorphisms in DNA-repair genes and cutaneous melanoma.

Mutat Res 2010 Sep 26;702(1):8-16. Epub 2010 Jun 26.

Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany.

Single-nucleotide polymorphisms in different DNA-repair genes are reported to modulate risk of various cancers including melanoma. We genotyped DNA from 1186 melanoma patients and 1280 healthy controls for 13 different polymorphisms in eight DNA-repair genes. Data analyses showed that none of the polymorphisms except T241M XRCC3 was associated with an increased risk for cutaneous melanoma. Carriers of the variant alleles were associated with a decreased risk (OR 0.83; 95% CI, 0.79-0.98). Three additional polymorphisms together with T241M XRCC3 that tagged the entire gene region and the neighbouring genes KLC1, ZFYVE21 and PPP1R13B were not associated with the disease risk; neither were the inferred haplotypes. Imputation showed association of comparable magnitude with 11 non-genotyped neighbouring polymorphisms. Finally, the combination of results for all polymorphisms genotyped in the present study with published data suggests that none of the investigated polymorphisms was associated with melanoma susceptibility. We conclude that 13 non-synonymous polymorphisms in eight DNA-repair genes that are frequently investigated with respect to modulation of cancer risk in populations are not associated with susceptibility to cutaneous melanoma.
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http://dx.doi.org/10.1016/j.mrgentox.2010.06.011DOI Listing
September 2010

Melanoma risk factors, perceived threat and intentional tanning: an international online survey.

Eur J Cancer Prev 2010 May;19(3):216-26

Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.

Cutaneous melanoma continues to increase in incidence in many countries, and intentional tanning is a risk factor for melanoma. The aim of this study was to understand how melanoma risk factors, perceived threat and preferences for a suntan relate to intentional tanning. Self-report data were collected on behalf of GenoMEL (www.genomel.org) from the general population using an online survey. A total of 8178 individuals completed the survey, with 72.8% of respondents being from Europe, 12.1% from Australia, 7.1% from the US, 2.5% from Israel and 5.5% from other countries. Seven percent of respondents had previously been diagnosed with melanoma and 8% had at least one first-degree relative with a previous melanoma. Overall, 70% reported some degree of intentional tanning during the past year, and 38% of respondents previously diagnosed with melanoma had intentionally tanned. The total number of risk factors was positively correlated with perceived risk of melanoma [correlation coefficient (rho) = 0.27], and negatively correlated with intentional tanning (rho = -0.16). Preference for a dark suntan was the strongest predictor of intentional tanning [regression coefficient (beta) = 0.35, P<0.001], even in those with a previous melanoma (beta = 0.33, P<0.01). A substantial proportion of participants reported having phenotypic and behavioural risk factors for melanoma. The preference regarding suntans seemed more important in the participants' decision to intentionally tan than their perceived risk of developing melanoma, and this finding was consistent among respondents from different countries. The drive to sunbathe to tan is a key factor to be moderated if melanoma incidence is to be reduced.
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http://dx.doi.org/10.1097/CEJ.0b013e3283354847DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3672405PMC
May 2010

Polymorphisms in the CD28/CTLA4/ICOS genes: role in malignant melanoma susceptibility and prognosis?

Cancer Immunol Immunother 2010 Feb;59(2):303-12

Erasmus Medical Center-Daniel den Hoed Cancer Center, Dr. Molewaterplein 50, 3015 GE Rotterdam, The Netherlands.

The appearance of vitiligo and spontaneous regression of the primary lesion in melanoma patients illustrate a relationship between tumor immunity and autoimmunity. T lymphocytes play a major role both in tumor immunity and autoimmunity. CD28, Cytotoxic T lymphocyte antigen 4 (CTLA4) and inducible costimulator (ICOS) molecules are important secondary signal molecules in the T lymphocyte activation. Single nucleotide polymorphisms (SNPs) in the CD28/CTLA4/ICOS gene region were reported to be associated with several autoimmune diseases including, type-1 diabetes, SLE, autoimmune thyroid diseases and celiac disease. In this study, we investigated the association of SNPs in the CD28, CTLA4 and ICOS genes with the risk of melanoma. We also assessed the prognostic effect of the different polymorphisms in melanoma patients. Twenty-four tagging SNPs across the three genes and four additional SNPs were genotyped in a cohort of 763 German melanoma patients and 734 healthy German controls. Influence on prognosis was determined in 587 melanoma cases belonging to stage I or II of the disease. In general, no differences in genotype or allele frequencies were detected between melanoma patients and controls. However, the variant alleles for two polymorphisms in the CD28 gene were differentially distributed in cases and controls. Similarly no association of any polymorphism with prognosis, except for the rs3181098 polymorphism in the CD28 gene, was observed. In addition, individuals with AA genotype for rs11571323 polymorphism in the ICOS gene showed reduced overall survival. However, keeping in view the correction for multiple hypothesis testing our results suggest that the polymorphisms in the CD28, CTLA4 and ICOS genes at least do not modulate risk of melanoma and nor do those influence the disease prognosis in the investigated population.
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http://dx.doi.org/10.1007/s00262-009-0751-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2776942PMC
February 2010

Melanocortin receptor 1 variants and melanoma risk: a study of 2 European populations.

Int J Cancer 2009 Oct;125(8):1868-75

Division of Molecular Genetic Epidemiology, German Cancer Research Center, 69120 Heidelberg, Germany.

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.
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http://dx.doi.org/10.1002/ijc.24548DOI Listing
October 2009

Reduced IFN-gamma- and enhanced IL-4-producing CD4+ cord blood T cells are associated with a higher risk for atopic dermatitis during the first 2 yr of life.

Pediatr Allergy Immunol 2010 Feb 23;21(1 Pt 1):5-13. Epub 2009 Jun 23.

UFZ-Helmholtz Centre for Environmental Research Leipzig, Department of Environmental Immunology, Leipzig, Germany.

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.
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http://dx.doi.org/10.1111/j.1399-3038.2009.00890.xDOI Listing
February 2010

Single nucleotide polymorphisms in DNA repair genes XRCC1 and APEX1 in progression and survival of primary cutaneous melanoma patients.

Mutat Res 2009 Feb 27;661(1-2):78-84. Epub 2008 Nov 27.

Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany.

Single nucleotide polymorphisms, besides influencing susceptibility can potentially alter progression and survival in melanoma patients. In this study we evaluated the association of polymorphisms in the base-excision repair genes XRCC1 and APEX1 with overall survival (OS), metastasis-free survival (MFS) and survival following the first metastasis (SFM) in patients with cutaneous melanoma. We genotyped the D148E APEX1, -77 T>C XRCC1, R280H XRCC1, and R399Q XRCC1 polymorphisms in 400 German melanoma patients (Tx, N0, M0) using an allelic discrimination method. The results were correlated with the patient follow-up parameters. The significant association detected between the R399Q XRCC1 polymorphism and MFS was also evaluated in 529 Spanish melanoma patients. In a Kaplan-Meier survival model the AA genotype of the polymorphism showed a median OS of 24.4 years compared to 11.5 years for two other genotypes. Similarly patients with the AA genotype showed median MFS of 20.9 years compared to 5.3 years for two other genotypes. In a multivariate Cox proportional hazard model, the AA genotype was associated with a hazard ratio (HR) of 0.40, 95% (CI 0.21-0.78, p=0.007) for MFS and 0.32 (95% CI 0.11-0.90, p=0.03) for OS in 400 German melanoma patients. The decreased risk of metastasis was confirmed by adding 529 Spanish melanoma patients with a combined HR of 0.40 (95% CI 0.24-0.68, p=0.0006). A significant association with SFM was also found for -77 T>C XRCC1 (HR 1.73, 95% CI 1.02-2.94, p=0.04). Our results show that non-synonymous variants or those located in potential regulatory regions of DNA repair genes probably influence the disease outcome in melanoma patients and have potentially significant implications for patient surveillance and tailored treatment.
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http://dx.doi.org/10.1016/j.mrfmmm.2008.11.011DOI Listing
February 2009

[First-line therapy in stage IV malignant melanoma].

Authors:
Adina Figl

J Dtsch Dermatol Ges 2007 Aug;5(8):725

Klinische Kooperationseinheit für Dermatoonkologie, DKFZ, Klinik für Dermatologie, Venerologie und Allergologie, Universitätsklinikums Mannheim, Mannheim, Germany.

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http://dx.doi.org/10.1111/j.1610-0387.2007.06486.xDOI Listing
August 2007

Multiple melanomas after treatment for Hodgkin lymphoma in a non-Dutch p16-Leiden mutation carrier with 2 MC1R high-risk variants.

Arch Dermatol 2007 Apr;143(4):495-9

Skin Cancer Unit, German Cancer Research Center, Heidelberg, Germany.

Background: A 19-base pair germline deletion in exon 2 of the CDKN2A (cyclin-dependent kinase inhibitor 2A) gene (Leiden mutation) has been detected in Dutch families with familial melanomas. The penetrance of CDKN2A mutations varies widely and is influenced by environmental and unrelated genetic factors such as variants in the MC1R gene.

Observations: We describe a 25-year-old German woman who developed 8 invasive melanomas and 6 in situ melanomas after radiation therapy and polychemotherapy for Hodgkin lymphoma. Genetic testing revealed a constitutional CDKN2A Leiden mutation in the proband and her sister, mother, and mother's sister. The proband also carried high-risk MC1R variant alleles R151C and R160W, which she had inherited from her father and her mother, respectively. The less affected mutation carrier sister did not have high-risk MC1R variant alleles. Analysis of DNA from paraffin-embedded tissues showed loss of heterozygosity at CDKN2A loci in all 3 melanomas studied but not in Hodgkin lymphoma. The pedigree revealed several types of cancers on both sides of the family, but no Dutch ancestors were found. No mutations in the CDK4, B-raf, and N-ras genes were detected either in the germline or in tumors from the patient.

Conclusion: This study shows the variability of the penetrance of the CDKN2A Leiden mutation within the same family, which could be due to genetic or exogenous factors.
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http://dx.doi.org/10.1001/archderm.143.4.495DOI Listing
April 2007