Katerina P. Kypreou

Genome-wide meta-analysis identifies five new susceptibility loci for cutaneous malignant melanoma

Thirteen common susceptibility loci have been reproducibly associated with cutaneous malignant melanoma (CMM). We report the results of an international 2-stage meta-analysis of CMM genome-wide association studies (GWAS). This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls. Five loci not previously associated with CMM risk reached genome-wide significance (P < 5 × 10−8), as did 2 previously reported but unreplicated loci and all 13 established loci. Newly associated SNPs fall within putative melanocyte regulatory elements, and bioinformatic and expression quantitative trait locus (eQTL) data highlight candidate genes in the associated regions, including one involved in telomere biology.

Comprehensive Field Synopsis and Systematic Meta-analyses of Genetic Association Studies in Cutaneous Melanoma

BACKGROUND Although genetic studies have reported a number of loci associated with cutaneous melanoma (CM) risk, a comprehensive synopsis of genetic association studies published in the field and systematic meta-analysis for all eligible polymorphisms have not been reported. METHODS We systematically annotated data from all genetic association studies published in the CM field (n = 145), including data from genome-wide association studies (GWAS), and performed random-effects meta-analyses across all eligible polymorphisms on the basis of four or more independent case-control datasets in the main analyses. Supplementary analyses of three available datasets derived from GWAS and GWAS-replication studies were also done. Nominally statistically significant associations between polymorphisms and CM were graded for the strength of epidemiological evidence on the basis of the Human Genome Epidemiology Network Venice criteria. All statistical tests were two-sided. RESULTS Forty-two polymorphisms across 18 independent loci evaluated in four or more datasets including candidate gene studies and available GWAS data were subjected to meta-analysis. Eight loci were identified in the main meta-analyses as being associated with a risk of CM (P < .05) of which four loci showed a genome-wide statistically significant association (P < 1 × 10(-7)), including 16q24.3 (MC1R), 20q11.22 (MYH7B/PIGU/ASIP), 11q14.3 (TYR), and 5p13.2 (SLC45A2). Grading of the cumulative evidence by the Venice criteria suggested strong epidemiological credibility for all four loci with genome-wide statistical significance and one additional gene at 9p23 (TYRP1). In the supplementary meta-analyses, a locus at 9p21.3 (CDKN2A/MTAP) reached genome-wide statistical significance with CM and had strong epidemiological credibility. CONCLUSIONS To the best of our knowledge, this is the first comprehensive field synopsis and systematic meta-analysis to identify genes associated with an increased susceptibility to CM.

Epidemiologic risk factors of basal cell carcinoma development and age at onset in a Southern European population from Greece.

Background:  Basal cell carcinoma (BCC) is the most common form of skin cancer with increasing incidence rates worldwide.

Comprehensive mutational analysis of CDKN2A and CDK4 in Greek patients with cutaneous melanoma.

Background  The penetrance of CDKN2A mutations is subject to geographical and latitudinal variation and is presumably dictated by ultraviolet radiation exposure and possibly other co‐inherited genetic factors. The frequency of mutations increases with the number of family members affected and the number of primary tumours, and also fluctuates with geography. To date, little is known about the prevalence of CDKN2A mutations in patients with melanoma from Greece.

Replication and predictive value of SNPs associated with melanoma and pigmentation traits in a Southern European case-control study.

Background Genetic association studies have revealed numerous polymorphisms conferring susceptibility to melanoma. We aimed to replicate previously discovered melanoma-associated single-nucleotide polymorphisms (SNPs) in a Greek case-control population, and examine their predictive value. Methods Based on a field synopsis of genetic variants of melanoma (MelGene), we genotyped 284 patients and 284 controls at 34 melanoma-associated SNPs of which 19 derived from GWAS. We tested each one of the 33 SNPs passing quality control for association with melanoma both with and without accounting for the presence of well-established phenotypic risk factors. We compared the risk allele frequencies between the Greek population and the HapMap CEU sample. Finally, we evaluated the predictive ability of the replicated SNPs. Results Risk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982 – SLC45A2, rs12203592 – IRF4, rs258322 – CDK10, rs1805007 – MC1R, rs1805008 - MC1R, rs910873 - PIGU, rs17305573- PIGU, and rs1885120 - MTAP) and higher for one SNP (rs6001027 – PLA2G6) indicating a different profile of genetic susceptibility in the studied population. Previously identified effect estimates modestly correlated with those found in our population (r = 0.72, P<0.0001). The strongest associations were observed for rs401681-T in CLPTM1L (odds ratio [OR] 1.60, 95% CI 1.22–2.10; P = 0.001), rs16891982-C in SCL45A2 (OR 0.51, 95% CI 0.34–0.76; P = 0.001), and rs1805007-T in MC1R (OR 4.38, 95% CI 2.03–9.43; P = 2×10−5). Nominally statistically significant associations were seen also for another 5 variants (rs258322-T in CDK10, rs1805005-T in MC1R, rs1885120-C in MYH7B, rs2218220-T in MTAP and rs4911442-G in the ASIP region). The addition of all SNPs with nominal significance to a clinical non-genetic model did not substantially improve melanoma risk prediction (AUC for clinical model 83.3% versus 83.9%, p = 0.66). Conclusion Overall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.

Updated field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma: the MelGene database.

We updated a field synopsis of genetic associations of cutaneous melanoma (CM) by systematically retrieving and combining data from all studies in the field published as of August 31, 2013. Data were available from 197 studies, which included 83,343 CM cases and 187,809 controls and reported on 1,126 polymorphisms in 289 different genes. Random-effects meta-analyses of 81 eligible polymorphisms evaluated in >4 data sets confirmed 20 single-nucleotide polymorphisms across 10 loci (TYR, AFG3L1P, CDK10, MYH7B, SLC45A2, MTAP, ATM, CLPTM1L, FTO, and CASP8) that have previously been published with genome-wide significant evidence for association (P<5 × 10(-8)) with CM risk, with certain variants possibly functioning as proxies of already tagged genes. Four other loci (MITF, CCND1, MX2, and PLA2G6) were also significantly associated with 5 × 10(-8)<P<1 × 10(-3). In supplementary meta-analyses derived from genome-wide association studies, one additional locus located 11 kb upstream of ARNT (chromosome 1q21) showed genome-wide statistical significance with CM. Our approach serves as a useful model in analyzing and integrating the reported germline alterations involved in CM.

A Pharmacogenetic Study of Psoriasis Risk Variants in a Greek Population and Prediction of Responses to Anti-TNF-α and Anti-IL-12/23 Agents

IntroductionPsoriasis is a highly divergent disease with many disease phenotypes, but there are currently no established biomarkers to predict the therapeutic outcomes of systemic treatments. With the introduction of biologic therapies during the last decade and with new treatments constantly emerging, there is a great need to validate biomarkers that have been reported to be associated with treatment response, and to introduce new biomarkers of possible clinical value.MethodsIn the current study, we aimed to investigate the association of psoriasis-related polymorphisms that have previously been reported to effect the anti-tumor necrosis factor alpha (anti-TNF-α) therapies (etanercept, adalimumab, and infliximab) and anti-interleukin-12/23 (anti-IL-12/23) biologic therapy (ustekinumab) in a Greek cohort of psoriasis patients.ResultsRs10484554 in the HLA-C gene showed an association with a good response to anti-TNF-α agents but not to ustekinumab, while rs151823 and rs26653 in the ERAP1 gene showed associations with a good response to anti-IL-12/23 therapy.ConclusionThis study is the first in the field of pharmacogenetics in Greek psoriasis patients. Further, larger studies are required to validate our findings and replicate them in various populations.

A Web-based database of genetic association studies in cutaneous melanoma enhanced with network-driven data exploration tools

The publicly available online database MelGene provides a comprehensive, regularly updated, collection of data from genetic association studies in cutaneous melanoma (CM), including random-effects meta-analysis results of all eligible polymorphisms. The updated database version includes data from 192 publications with information on 1114 significantly associated polymorphisms across 280 genes, along with new front-end and back-end capabilities. Various types of relationships between data are calculated and visualized as networks. We constructed 13 different networks containing the polymorphisms and the genes included in MelGene. We explored the derived network representations under the following questions: (i) are there nodes that deserve consideration regarding their network connectivity characteristics? (ii) What is the relation of either the genome-wide or nominally significant CM polymorphisms/genes with the ones highlighted by the network representation? We show that our network approach using the MelGene data reveals connections between statistically significant genes/ polymorphisms and other genes/polymorphisms acting as ‘hubs’ in the reconstructed networks. To the best of our knowledge, this is the first database containing data from a comprehensive field synopsis and systematic meta-analyses of genetic polymorphisms in CM that provides user-friendly tools for in-depth molecular network visualization and exploration. The proposed network connections highlight potentially new loci requiring further investigation of their relation to melanoma risk. Database URL: http://www.melgene.org.

Association of Melanocortin-1 Receptor Variants with Pigmentary Traits in Humans: A Pooled Analysis from the M-Skip Project

Bishop, J; Polsky, D; Lazovich, D; Kumar, R; Ghiorzo, P; Ferrucci, L; Gruis, NA; Puig, S; Kanetsky, PA; Motokawa, T; Ribas, G; Landi, MT; Fargnoli, MC; Wong, TH; Stratigos, A; Helsing, P; Guida, G; Autier, P; Han, J; Little, J; Sera, F; Raimondi, S; M-SKIP Study group, ; , COLLABORATORS; Raimondi, S; Autier, P; Fargnoli, MC; Garca-Borrn, JC; Han, J; Kanetsky, PA; Landi, MT; Little, J; Newton-Bishop, J; Sera, F; Caini, S; Gandini, S; Maisonneuve, P; Hofman, A; Kayser, M; Liu, F; Nijsten, T; Uitterlinden, AG; Kumar, R; Scherer, D; Bishop, T; Newton-Bishop, J; Elliott, F; Nagore, E; Lazovich, D; Polsky, D; Hansson, J; Hoiom, V; Ghiorzo, P; Pastorino, L; Gruis, NA; Bouwes Bavinck, JN; Aguilera, P; Badenas, C; Carrera, C; Gimenez-Xavier, P; Malvehy, J; Potrony, M; Puig, S; Puig-Butille, JA; Tell-Marti, G; Dwyer, T; Blizzard, L; Cochrane, J; Fernandez-de-Misa, R; Branicki, W; Debniak, T; Morling, N; Johansen, P; Mayne, S; Bale, A; Cartmel, B; Ferrucci, L; Pfeiffer, R; Palmieri, G; Ribas, G; Menin, C; Stratigos, A; Kypreou, K; Bowcock, A; Cornelius, L; Council, ML; Motokawa, T; Anno, S; Helsing, P; Andresen, PA; Guida, G; Guida, S; Wong, TH (2016) Association of Melanocortin-1 Receptor Variants with Pigmentary Traits in Humans: A Pooled-Analysis from the M-SKIP Project. The Journal of investigative dermatology, 136 (9). pp. 1914-7. ISSN 0022-202X DOI: https://doi.org/10.1016/j.jid.2016.05.099

Replication of risk variants for psoriasis in a Southern European case–control study: correlation with clinical subphenotypes

DEAR EDITOR, Psoriasis subtypes are defined by the morphology of lesions and by age at disease onset, with type 1 appearing before and type 2 after the age of 40 years. Psoriasis can also have extracutaneous manifestations such as psoriatic arthritis and nail involvement; it has also been associated with other inflammatory diseases such as metabolic syndrome and cardiovascular disease, possibly through common genetic pathways. Recently, genome-wide association studies (GWAS) have implicated several polymorphisms that are involved in the innate and adaptive immune system, and inflammation, in the pathogenesis of psoriasis. There is still a lack of understanding of the possible association between each individual risk allele with specific clinical subphenotypes and comorbidities. Furthermore, the majority of studies involve people of European descent, while studies conducted in Asian populations often yield different results, echoing variations in genetic background and disease prevalence. We sought to replicate systematically robust findings from psoriasis GWAS in a substantial Greek cohort and to assess the effect of these variants in relevant subphenotypes and comorbidities. The study population consisted of 504 Greek patients with psoriasis and 505 control participants, above the age of 18 years. Cases were diagnosed by a dermatologist at Andreas Syggros Hospital, did not suffer from any other immune diseases or malignancies, and had psoriatic lesions for at least 6 months prior to the study. The control sample consisted of individuals with minor skin diseases, or hospital staff members without a history or evidence of psoriasis, malignancies or immune diseases. The principles of the Declaration of Helsinki were followed, and the hospital’s scientific and ethics committee approved the research protocol. All participants gave written informed consent. We selected all variants that were robustly associated in GWAS or candidate gene studies in populations of European descent published up to October 2012. These single nucleotide polymorphisms (SNPs) are significantly associated with psoriasis at a genome-wide level (P < 5 9 10 ). Genomic DNA was isolated from peripheral blood using the QIAamp DNA Blood Mini Kit (Qiagen, Hilden, Germany). A total of 50 ng from each DNA sample was used for genotyping using the iPLEX assay (Sequenom, Hamburg, Germany). We accepted for further analysis SNPs with a call rate of > 98%. SNPs should not deviate from Hardy–Weinberg equilibrium in controls using a v test (P > 0 05). Using a logistic regression analysis assuming a multiplicative model of inheritance, we calculated the association of each SNP with psoriasis. In all cases, the minor allele was used as the reference allele. We estimated the odds ratios (OR) and 95% confidence intervals. Moreover, we performed subgroup analysis in different types of psoriasis (psoriasis type 1 or 2, psoriatic