| 1. |
- Artomov, Mykyta, et al.
(författare)
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Rare variant, gene-based association study of hereditary melanoma using whole-exome sequencing
- 2017
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Ingår i: Journal of the National Cancer Institute. - : Oxford University Press (OUP). - 0027-8874 .- 1460-2105. ; 109:12
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Tidskriftsartikel (refereegranskat)abstract
- Background: Extraordinary progress has been made in our understanding of common variants in many diseases, including melanoma. Because the contribution of rare coding variants is not as well characterized, we performed an exome-wide, gene-based association study of familial cutaneous melanoma (CM) and ocular melanoma (OM). Methods: Using 11 990 jointly processed individual DNA samples, whole-exome sequencing was performed, followed by largescale joint variant calling using GATK (Genome Analysis ToolKit). PLINK/SEQ was used for statistical analysis of genetic variation. Fourmodels were used to estimate the association among different types of variants. In vitro functional validation was performed using three humanmelanoma cell lines in 2D and 3D proliferation assays. In vivo tumor growth was assessed using xenografts of humanmelanoma A375melanoma cells in nudemice (eightmice per group). All statistical tests were two-sided. Results: Strong signals were detected for CDKN2A (Pmin = 6.16×10-8) in the CM cohort (n=273) and BAP1 (Pmin = 3.83×10-6) in the OM (n=99) cohort. Eleven genes that exhibited borderline association (P < 10-4) were independently validated using The Cancer Genome Atlas melanoma cohort (379 CM, 47 OM) and a matched set of 3563 European controls with CDKN2A (P = .009), BAP1 (P = .03), and EBF3 (P = 4.75×10-4), a candidate risk locus, all showing evidence of replication. EBF3 was then evaluated using germline data from a set of 132 familial melanoma cases and 4769 controls of UK origin (joint P = 1.37×10-5). Somatically, loss of EBF3 expression correlated with progression, poorer outcome, and high MITF tumors. Functionally, induction of EBF3 in melanoma cells reduced cell growth in vitro, retarded tumor formation in vivo, and reduced MITF levels. Conclusions: The results of this large rare variant germline association study further define the mutational landscape of hereditary melanoma and implicate EBF3 as a possible CM predisposition gene.
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| 2. |
- Bradbury, Kathryn E., et al.
(författare)
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Circulating insulin-like growth factor I in relation to melanoma risk in the European prospective investigation into cancer and nutrition
- 2019
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Ingår i: International Journal of Cancer. - : John Wiley & Sons. - 0020-7136 .- 1097-0215. ; 144:5, s. 957-966
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Tidskriftsartikel (refereegranskat)abstract
- Insulin-like growth factor-I (IGF-I) regulates cell proliferation and apoptosis, and is thought to play a role in tumour development. Previous prospective studies have shown that higher circulating concentrations of IGF-I are associated with a higher risk of cancers at specific sites, including breast and prostate. No prospective study has examined the association between circulating IGF-I concentrations and melanoma risk. A nested case-control study of 1,221 melanoma cases and 1,221 controls was performed in the European Prospective Investigation into Cancer and Nutrition cohort, a prospective cohort of 520,000 participants recruited from 10 European countries. Conditional logistic regression was used to estimate odds ratios (ORs) for incident melanoma in relation to circulating IGF-I concentrations, measured by immunoassay. Analyses were conditioned on the matching factors and further adjusted for age at blood collection, education, height, BMI, smoking status, alcohol intake, marital status, physical activity and in women only, use of menopausal hormone therapy. There was no significant association between circulating IGF-I concentration and melanoma risk (OR for highest vs lowest fifth = 0.93 [95% confidence interval [CI]: 0.71 to 1.22]). There was no significant heterogeneity in the association between IGF-I concentrations and melanoma risk when subdivided by gender, age at blood collection, BMI, height, age at diagnosis, time between blood collection and diagnosis, or by anatomical site or histological subtype of the tumour (Pheterogeneity≥0.078). We found no evidence for an association between circulating concentrations of IGF-I measured in adulthood and the risk of melanoma.
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| 3. |
- Davies, John R., et al.
(författare)
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An inherited variant in the gene coding for vitamin D-binding protein and survival from cutaneous melanoma: a BioGenoMEL study
- 2014
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Ingår i: Pigment Cell & Melanoma Research. - : Wiley. - 1755-148X .- 1755-1471. ; 27:2, s. 234-243
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Tidskriftsartikel (refereegranskat)abstract
- An association between low serum vitamin D levels and poorer melanoma survival has been reported. We have studied inheritance of a polymorphism of the GC gene, rs2282679, coding for the vitamin D-binding protein, which is associated with lower serum levels of vitamin D, in a meta-analysis of 3137 melanoma patients. The aim was to investigate evidence for a causal relationship between vitamin D and outcome (Mendelian randomization). The variant was not associated with reduced overall survival (OS) in the UK cohort, per-allele hazard ratio (HR) for death 1.23 (95% confidence interval (CI) 0.93, 1.64). In the smaller cohorts, HR in OS analysis was 1.07 (95% CI 0.88, 1.3) and for all cohorts combined, HR for OS was 1.09 (95% CI 0.93, 1.29). There was evidence of increased melanoma-specific deaths in the seven cohorts for which these data were available. The lack of unequivocal findings despite the large sample size illustrates the difficulties of implementing Mendelian randomization.
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| 4. |
- Davies, John R, et al.
(författare)
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Inherited variation in the PARP1 gene and survival from melanoma
- 2014
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136 .- 1097-0215. ; 135:7, s. 1625-1633
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Tidskriftsartikel (refereegranskat)abstract
- We report the association of an inherited variant located upstream of the poly(adenosine diphosphate-ribose) polymerase 1 (PARP1) gene (rs2249844), with survival in 11 BioGenoMEL melanoma cohorts. The gene encodes a protein involved in a number of cellular processes including single-strand DNA repair. Survival analysis was conducted for each cohort using proportional hazards regression adjusting for factors known to be associated with survival. Survival was measured as overall survival (OS) and, where available, melanoma-specific survival (MSS). Results were combined using random effects meta-analysis. Evidence for a role of the PARP1 protein in melanoma ulceration and survival was investigated by testing gene expression levels taken from formalin-fixed paraffin-embedded tumors. A significant association was seen for inheritance of the rarer variant of PARP1, rs2249844 with OS (hazard ratio (HR) = 1.16 per allele, 95% confidence interval (CI) 1.04-1.28, p=0.005, eleven cohorts) and MSS (HR=1.20 per allele, 95% CI 1.01-1.39, p=0.03, eight cohorts). We report bioinformatic data supportive of a functional effect for rs2249844. Higher levels of PARP1 gene expression in tumors were shown to be associated with tumor ulceration and poorer OS. What's new? Although staging systems predict outcome fairly well for melanoma, survival still varies among individual patients. In this meta-analysis, the authors found that inheritance of a rare genetic variant of PARP1 was associated with improved survival of melanoma patients. Increased expression of PARP1 has been associated with poorer outcome, and depletion of PARP1 may reduce both melanoma growth and angiogenesis. The identification of this and other germline variants that affect survival may help to identify key biological pathways active in host/tumor interactions, which may lead to the discovery of new therapeutic targets for treating advanced melanoma. Epidemiology
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| 5. |
- Forsea, Ana-Maria, et al.
(författare)
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Inequalities in the patterns of dermoscopy use and training across Europe : conclusions of the Eurodermoscopy pan-European survey
- 2020
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Ingår i: European journal of dermatology : EJD. - : John Libbey Eurotext. - 1167-1122 .- 1952-4013. ; 30:5, s. 524-531
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Dermoscopy is a widely used technique, recommended in clinical practice guidelines worldwide for the early diagnosis of skin cancers. Intra-European disparities are reported for early detection and prognosis of skin cancers, however, no information exists about regional variation in patterns of dermoscopy use across Europe.OBJECTIVE: To evaluate the regional differences in patterns of dermoscopy use and training among European dermatologists.MATERIALS & METHODS: An online survey of European-registered dermatologists regarding dermoscopy training, practice and attitudes was established. Answers from Eastern (EE) versus Western European (WE) countries were compared and their correlation with their respective countries' gross domestic product/capita (GDPc) and total and government health expenditure/capita (THEc and GHEc) was analysed.RESULTS: We received 4,049 responses from 14 WE countries and 3,431 from 18 EE countries. A higher proportion of WE respondents reported dermoscopy use (98% vs. 77%, p<0.001) and training during residency (43% vs. 32%) or anytime (96.5% vs. 87.6%) (p<0.001) compared to EE respondents. The main obstacles in dermoscopy use were poor access to dermoscopy equipment in EE and a lack of confidence in one's skills in WE. GDPc, THEc and GHEc correlated with rate of dermoscopy use and dermoscopy training during residency (Spearman rho: 0.5-0.7, p<0.05), and inversely with availability of dermoscopy equipment.CONCLUSION: The rates and patterns of dermoscopy use vary significantly between Western and Eastern Europe, on a background of economic inequality. Regionally adapted interventions to increase access to dermoscopy equipment and training might enhance the use of this technique towards improving the early detection of skin cancers.
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| 6. |
- Liopyris, Konstantinos, et al.
(författare)
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Expert agreement on the presence and spatial localization of melanocytic features in dermoscopy.
- 2023
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Ingår i: The Journal of investigative dermatology. - 1523-1747. ; 144:3
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Tidskriftsartikel (refereegranskat)abstract
- Dermoscopy aids in melanoma detection; however, agreement on dermoscopic features, including those of high clinical relevance, remains poor. Herein we attempted to evaluate agreement among experts on 'exemplar images' not only for the presence of melanocytic-specific features but also for spatial localization. This was a cross-sectional, multicenter, observational study. Dermoscopy images exhibiting at least one of 31 melanocytic-specific features were submitted by 25 world experts as 'exemplars'. Using a web-based platform that allows for image mark-up of specific contrast-defined regions (superpixels), 20 expert readers annotated 248 dermoscopic images in collections of 62 images. Each collection was reviewed by five independent readers. A total of 4,507 feature observations were performed. Good-to-excellent agreement was found for 14 of 31 features (45.2%), with 8 achieving excellent agreement (Gwet's AC >0.75) and 7 of them being melanoma-specific features. These features were: 'Peppering /Granularity' (0.91); 'Shiny White Streaks' (0.89); 'Typical Pigment network' (0.83); 'Blotch Irregular' (0.82); 'Negative Network' (0.81); 'Irregular Globules' (0.78); 'Dotted Vessels' (0.77) and 'Blue Whitish Veil' (0.76). By utilizing an exemplar dataset, good-to-excellent agreement was found for 14 features that have previously been shown useful in discriminating nevi from melanoma. All images are public (www.isic-archive.com) and can be used for education, scientific communication and machine learning experiments.
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| 7. |
- Trakatelli, Myrto, et al.
(författare)
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Clinical assessment of skin phototypes: watch your words!
- 2017
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Ingår i: European journal of dermatology : EJD. - : John Libbey Eurotext. - 1952-4013 .- 1167-1122. ; 27:6, s. 615-619
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Tidskriftsartikel (refereegranskat)abstract
- Fitzpatrick skin phototype classification is widely used to assess risk factors for skin cancers. This skin type evaluation is easy to use in clinical practice but is not always applied as initially described, nor practiced in a standardised way. This can have implications on the results of relevant dermato-epidemiological studies. To demonstrate, in a large multinational setting, that the phrasing of questions on sun sensitivity can have a strong impact on the perception and reporting of skin phototype, as well as the importance of a standardised procedure for phototype assessment. Using data collected from 48,258 screenees of the Euromelanoma campaign in six European countries from 2009 to 2011, we analysed the impact of change in the question phrasing on phototype classification in each country. Changing the wording of a question to assess the phototype of a person also significantly influenced the classification of phototypes in different countries (p<0.001 for each country). The difference essentially corresponded to a shift towards a less sun-sensitive skin type when a shorter question that did not include skin colour description was used. The only exception was Portugal where phototype was not patient-assessed and classification shifted towards a more sun-sensitive phototype. Results were statistically significant and highly consistent, irrespective of gender. The phrasing of questions on skin type is important and substantially influences reporting. A standardized procedure to classify phototypes should be used in order to obtain comparable data between studies.
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