| 1. |
- Hudson, Lawrence N, et al.
(författare)
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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project
- 2017
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Ingår i: Ecology and Evolution. - : John Wiley & Sons. - 2045-7758. ; 7:1, s. 145-188
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Tidskriftsartikel (refereegranskat)abstract
- The PREDICTS project-Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)-has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity.
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| 2. |
- 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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| 3. |
- 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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| 4. |
- Denisova, Evgeniya, et al.
(författare)
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Frequent DPH3 promoter mutations in skin cancers.
- 2015
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 6:34, s. 35922-35930
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Tidskriftsartikel (refereegranskat)abstract
- Recent reports suggested frequent occurrence of cancer associated somatic mutations within regulatory elements of the genome. Based on initial exome sequencing of 21 melanomas, we report frequent somatic mutations in skin cancers in a bidirectional promoter of diphthamide biosynthesis 3 (DPH3) and oxidoreductase NAD-binding domain containing 1 (OXNAD1) genes. The UV-signature mutations occurred at sites adjacent and within a binding motif for E-twenty six/ternary complex factors (Ets/TCF), at -8 and -9 bp from DPH3 transcription start site. Follow up screening of 586 different skin lesions showed that the DPH3 promoter mutations were present in melanocytic nevi (2/114; 2%), melanoma (30/304; 10%), basal cell carcinoma of skin (BCC; 57/137; 42%) and squamous cell carcinoma of skin (SCC; 12/31; 39%). Reporter assays carried out in one melanoma cell line for DPH3 and OXNAD1 orientations showed statistically significant increased promoter activity due to -8/-9CC > TT tandem mutations; although, no effect of the mutations on DPH3 and OXNAD1 transcription in tumors was observed. The results from this study show occurrence of frequent somatic non-coding mutations adjacent to a pre-existing binding site for Ets transcription factors within the directional promoter of DPH3 and OXNAD1 genes in three major skin cancers. The detected mutations displayed typical UV signature; however, the functionality of the mutations remains to be determined.
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| 5. |
- Heidenreich, Barbara, et al.
(författare)
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Telomerase reverse transcriptase promoter mutations in primary cutaneous melanoma.
- 2014
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5:Feb 26
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Tidskriftsartikel (refereegranskat)abstract
- We previously reported a disease segregating causal germline mutation in a melanoma family and recurrent somatic mutations in metastasized tumours from unrelated patients in the core promoter region of the telomerase reverse transcriptase (TERT) gene. Here we show that the TERT promoter mutations, besides causing an increased gene expression, associate with increased patient age, increased Breslow thickness and tumour ulceration in 287 primary melanomas. The mutations are more frequent at both intermittently and chronically sun-exposed sites than non-exposed sites and tend to co-occur with BRAF and CDKN2A alterations. The association with parameters generally connected with poor outcome, coupled with high recurrence and mechanistic relevance, raises the possibility of the eventual use of TERT promoter mutations in the disease management.
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| 6. |
- Horn, Susanne, et al.
(författare)
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TERT Promoter Mutations in Familial and Sporadic Melanoma
- 2013
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 1095-9203 .- 0036-8075. ; 339:6122, s. 959-961
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Tidskriftsartikel (refereegranskat)abstract
- 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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| 7. |
- Iles, Mark M., et al.
(författare)
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A variant in FTO shows association with melanoma risk not due to BMI
- 2013
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 45:4, s. 428-432
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Tidskriftsartikel (refereegranskat)abstract
- We report the results of an association study of melanoma that is based on the genome-wide imputation of the genotypes of 1,353 cases and 3,566 controls of European origin conducted by the GenoMEL consortium. This revealed an association between several SNPs in intron 8 of the FTO gene, including rs16953002, which replicated using 12,313 cases and 55,667 controls of European ancestry from Europe, the USA and Australia (combined P = 3.6 x 10(-12), per-allele odds ratio for allele A = 1.16). In addition to identifying a new melanomasusceptibility locus, this is to our knowledge the first study to identify and replicate an association with SNPs in FTO not related to body mass index (BMI). These SNPs are not in intron 1 (the BMI-related region) and exhibit no association with BMI. This suggests FTO's function may be broader than the existing paradigm that FTO variants influence multiple traits only through their associations with BMI and obesity.
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| 8. |
- Maccioni, Livia, et al.
(författare)
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Variants at chromosome 20 (ASIP locus) and melanoma risk
- 2013
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 132:1, s. 42-54
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Tidskriftsartikel (refereegranskat)abstract
- Agouti signaling protein (ASIP) locus on chromosome 20q11 is implicated, as shown by genome-wide association studies, in phenotype variation and melanoma risk. We genotyped 837 melanoma cases and 1,154 controls for 21 single nucleotide polymorphisms (SNPs) informative for 495 polymorphisms at the locus. Our data showed an increased risk of melanoma (odds ratio [OR] 1.27, 95% confidence interval [95% CI] 1.03-1.57) in carriers of the rs4911414 variant, located 120 kb upstream of ASIP. The main effect of rs4911414, as reported previously, was in tandem with a 10 kb adjacent polymorphism rs1015362; two constituted risk-associated haplotype/diplotype. Except for rs1015363, none of the 12 tagging SNPs, genotyped to cover 239.9 kb region with polymorphisms linked to rs4911414 and rs1015362, were associated with melanoma. Our data confirmed a previous association of melanoma risk (OR 1.82, 95% CI 1.37-2.41) with rs4911442, located in intron 5 of the nuclear receptor coactivator 6 (NCOA6) gene. The rs910871, one of the six variants, genotyped to cover NCOA6, showed an association with melanoma risk (OR 1.33, 95% CI 1.04-1.70). Both, rs4911442 and rs910871 were in moderate linkage with a, previously reported, risk-associated rs910873 polymorphism. A haplotype from the variants within NCOA6 showed an association with risk of melanoma (OR 1.49, 95% CI 1.17-1.88). Interaction between risk-associated polymorphisms and previously genotyped melanocortin receptor 1 (MC1R) variants, in our study, was not statistically significant. Nevertheless, the carriers of the variant alleles over the background of MC1R variants were at a higher risk than the carriers not enriched for MC1R variants. Our data confirmed the association of different variants at chromosome 20q11 with melanoma risk.
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| 9. |
- Maccioni, Livia, et al.
(författare)
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Variants at the 9p21 locus and melanoma risk
- 2013
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Ingår i: BMC Cancer. - : Springer Science and Business Media LLC. - 1471-2407. ; 13
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Tidskriftsartikel (refereegranskat)abstract
- Background: The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS). Methods: In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region. Results: All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3' UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A-allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54). Conclusions: Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes.
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| 10. |
- Nagore, Eduardo, et al.
(författare)
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TERT promoter mutations in melanoma survival.
- 2016
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Ingår i: International Journal of Cancer. - : Wiley. - 0020-7136. ; 139:1, s. 75-84
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Tidskriftsartikel (refereegranskat)abstract
- Despite advances in targeted therapies, the treatment of advanced melanoma remains an exercise in disease management, hence a need for biomarkers for identification of at risk primary melanoma patients. In this study we aimed to assess the prognostic value of TERT promoter mutations in primary melanomas. DNA from 300 patients with stage I/II melanoma was sequenced for TERT promoter and BRAF/NRAS mutations. Cumulative curves were drawn for patients with and without mutations with progression free and melanoma specific survival as outcomes. Cox proportional hazard regression models were used to determine the effect of the mutations on survivals. Individually, presence of TERT promoter and BRAF/NRAS mutations associated with poor disease free and melanoma specific survival with modification of the effect by the rs2853669 polymorphism within the TERT promoter. Hazard ratio (HR) for simultaneous occurrence of TERT promoter and BRAF/NRAS mutations for disease free survival was 2.25 (95%CI 1.2-4.4) and for melanoma specific survival 5.8 (95%CI 1.8-18.1). The effect of the mutations on melanoma-specific survival in non-carriers of variant allele of the polymorphism was significant (HR 4.4, 95%CI 1.3-14.9) but could not be calculated for the carriers due to low number of events. The variant allele per se showed association with increased survival (HR 0.4, 95%CI 0.1-0.9). The data in this study provides preliminary evidence that TERT promoter mutations in combination with BRAF/NRAS mutations can be used to identify patients at risk of aggressive disease and the possibility of refinement of the classification with inclusion of the rs2853669 polymorphism within TERT promoter. This article is protected by copyright. All rights reserved.
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| 11. |
- Stacey, Simon N, et al.
(författare)
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A germline variant in the TP53 polyadenylation signal confers cancer susceptibility.
- 2011
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 43:11, s. 1098-103
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Tidskriftsartikel (refereegranskat)abstract
- To identify new risk variants for cutaneous basal cell carcinoma, we performed a genome-wide association study of 16 million SNPs identified through whole-genome sequencing of 457 Icelanders. We imputed genotypes for 41,675 Illumina SNP chip-typed Icelanders and their relatives. In the discovery phase, the strongest signal came from rs78378222[C] (odds ratio (OR) = 2.36, P = 5.2 × 10(-17)), which has a frequency of 0.0192 in the Icelandic population. We then confirmed this association in non-Icelandic samples (OR = 1.75, P = 0.0060; overall OR = 2.16, P = 2.2 × 10(-20)). rs78378222 is in the 3' untranslated region of TP53 and changes the AATAAA polyadenylation signal to AATACA, resulting in impaired 3'-end processing of TP53 mRNA. Investigation of other tumor types identified associations of this SNP with prostate cancer (OR = 1.44, P = 2.4 × 10(-6)), glioma (OR = 2.35, P = 1.0 × 10(-5)) and colorectal adenoma (OR = 1.39, P = 1.6 × 10(-4)). However, we observed no effect for breast cancer, a common Li-Fraumeni syndrome tumor (OR = 1.06, P = 0.57, 95% confidence interval 0.88-1.27).
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| 12. |
- Taylor, Nicholas J, et al.
(författare)
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Estimating CDKN2A mutation carrier probability among global familial melanoma cases using GenoMELPREDICT
- 2019
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Ingår i: Journal of the American Academy of Dermatology. - : Elsevier BV. - 0190-9622 .- 1097-6787. ; 81:2, s. 386-394
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although rare in the general population, highly penetrant germline mutations in CDKN2A are responsible for 5-40% of melanoma cases reported in melanoma-prone families. We sought to determine whether MELPREDICT was generalizable to a global series of melanoma families and whether performance improvements can be achieved.METHODS: 2,116 familial melanoma cases were ascertained by the international GenoMEL Consortium. We recapitulated the MELPREDICT model within our data (GenoMELPREDICT) to assess performance improvements by adding phenotypic risk factors and history of pancreatic cancer. We report areas under the curve (AUC) with 95% confidence intervals (CI) along with net reclassification indices (NRI) as performance metrics.RESULTS: MELPREDICT performed well (AUC=0.752; 95%CI: 0.730, 0.775), and GenoMELPREDICT performance was similar (AUC=0.748; 95% CI: 0.726, 0.771). Adding a reported history of pancreatic cancer yielded discriminatory improvement (p<0.0001) in GenoMELPREDICT (AUC=0.772; 95%CI: 0.750, 0.793; NRI=0.40). Including phenotypic risk factors did not improve performance.CONCLUSION: The MELPREDICT model functioned well in a global dataset of familial melanoma cases. Adding pancreatic cancer history improved model prediction. GenoMELPREDICT is a simple tool for predicting CDKN2A mutational status among melanoma patients from melanoma-prone families and can aid in counselling these patients towards genetic testing or cancer risk counselling.
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| 13. |
- Taylor, Nicholas J., et al.
(författare)
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Germline Variation at CDKN2A and Associations with Nevus Phenotypes among Members of Melanoma Families
- 2017
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Ingår i: Journal of Investigative Dermatology. - : Elsevier BV. - 0022-202X .- 1523-1747. ; 137:12, s. 2606-2612
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Tidskriftsartikel (refereegranskat)abstract
- Germline mutations in CDKN2A are frequently identified among melanoma kindreds and are associated with increased atypical nevus counts. However, a clear relationship between pathogenic CDKN2A mutation carriage and other nevus phenotypes including counts of common acquired nevi has not yet been established. Using data from GenoMEL, we investigated the relationships between CDKN2A mutation carriage and 2-mm, 5-mm, and atypical nevus counts among blood-related members of melanoma families. Compared with individuals without a pathogenic mutation, those who carried one had an overall higher prevalence of atypical (odds ratio = 1.64; 95% confidence interval = 1.18–2.28) nevi but not 2-mm nevi (odds ratio = 1.06; 95% confidence interval = 0.92–1.21) or 5-mm nevi (odds ratio = 1.26; 95% confidence interval = 0.94–1.70). Stratification by case status showed more pronounced positive associations among non-case family members, who were nearly three times (odds ratio = 2.91; 95% confidence interval = 1.75–4.82) as likely to exhibit nevus counts at or above the median in all three nevus categories simultaneously when harboring a pathogenic mutation (vs. not harboring one). Our results support the hypothesis that unidentified nevogenic genes are co-inherited with CDKN2A and may influence carcinogenesis.
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| 14. |
- 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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| 15. |
- Xie, Huaping, et al.
(författare)
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Mapping of deletion breakpoints at the CDKN2A locus in melanoma: detection of MTAP-ANRIL fusion transcripts.
- 2016
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Ingår i: Oncotarget. - : Impact Journals, LLC. - 1949-2553. ; 7:13, s. 16490-16504
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Tidskriftsartikel (refereegranskat)abstract
- Genomic locus at chromosome 9p21 that contains the CDKN2A and CDKN2B tumor suppressor genes is inactivated through mutations, deletions and promoter methylation in multiple human cancers. Additionally, the locus encodes an anti-sense RNA (ANRIL). Both hemizygous and homozygous deletions at the locus targeting multiple genes are fairly common in different cancers. We in this study investigated breakpoints in five melanoma cell lines, derived from metastasized tumors, with previously identified homozygous deletions using array comparative genomic hybridization (aCGH). For breakpoint mapping, we used primer approximation multiplex PCR (PAMP) and inverse PCR techniques. Our results showed that three cell lines carried complex rearrangements. In two other cell lines, with focal deletions of 141 kb and 181 kb, we identified fusion gene products, involving MTAP and ANRIL. We also confirmed the complex rearrangements and focal deletions in DNA from tumor tissues corresponding to three cell lines. The rapid amplification of 3'cDNA ends (3'RACE) carried out on transcripts resulted in identification of three isoforms of MTAP-ANRIL fusion gene. Screening of cDNA from 64 melanoma cell lines resulted in detection of fusion transcripts in 13 (20%) cell lines that involved exons 4-7 of the MTAP and exon 2 or 5 of the ANRIL genes. We also detected fusion transcripts involving MTAP and ANRIL in two of the seven primary melanoma tumors with focal deletion at the locus. The results from the study, besides identifying complex rearrangements involving CDKN2A locus, show frequent occurrence of fusion transcripts involving MTAP and ANRIL genes.
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