Irene Stefanaki

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.

Melanoma/skin cancer screening in a Mediterranean country: results of the Euromelanoma Screening Day Campaign in Greece.

Background  Since the year 2000 a melanoma/skin cancer screening campaign has been organized annually in Greece in the context of the Euromelanoma Screening Day Campaign.

p53 codon 72 Pro homozygosity increases the risk of cutaneous melanoma in individuals with dark skin complexion and among noncarriers of melanocortin 1 receptor red hair variants

Background  p53 has a common polymorphism at amino acid 72, encoding either arginine or proline. p53Arg and p53Pro exhibit differences in various biological activities, such as cell‐cycle arrest and induction of apoptosis. Numerous epidemiological studies have examined the role of this polymorphism in several human malignancies, including cutaneous cancers, with contradictory results.

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.

The Greek experience with efalizumab in psoriasis from a University Dermatologic Hospital.

Background  Efalizumab (anti‐CD11a antibody) targets T cell‐mediated steps important in the immunopathogenesis of psoriasis. As efalizumab is intended to be administered on a continuous long‐term basis in psoriasis, it is important to share experience concerning issues commonly occurring during its use in real daily practice.

Pregnancy during adalimumab use for psoriasis

Editor As more biological medications become available to treat psoriasis, the number of women who conceive during treatment will increase. When evaluating medications in women who become pregnant, it is important for dermatologists to accurately address the complications for the child. We report a 34-year-old woman who inadvertently became pregnant during adalimumab therapy, despite the fact that she had been counselled about using contraception. She received adalimumab for psoriasis with excellent response for 3 months prior to conception and during 5 weeks of gestation. Amniocentesis failed to detect any anomaly. The patient had an elective caesarean section performed at 38.5 weeks, and a low-birth-weight newborn was delivered. The child has normal development at 12 months follow-up. Data regarding the use of anti-TNF therapy during pregnancy come from rheumatology and gastroenterology. Most reports regard women with Crohn’s disease (CD) or rheumatic disease [reumatoid arthritis (RA), psoriatic arthritis, spondylarthritis (SpA), juvenile idiopathic arthritis (JIA)], and suggest that infliximab or etanercept treatment during the first trimester does not lead to an increased rate of birth defects, miscarriages or preterm delivery. In 23 women with rheumatic diseases exposed to anti-TNF-a (etanercept, infliximab, adalimumab) during first trimester, there were 6 spontaneous miscarriages (26%), 3 elective terminations and 14 live births. Of note, there was an increased risk for preterm delivery and lower birth weight in women with RA, regardless of medication. There are few reports of anti-TNF-a continued throughout pregnancy. In 10 women with CD who received infliximab throughout pregnancy, all had live births, with three premature deliveries and one low-birth-weight infant, with no congenital malformations. Women with rheumatic disease were exposed to infliximab or etanercept throughout pregnancy with no complications. There are 10 reported pregnancies with adalimumab use (Table 1). The molecular structure of adalimumab (IgG1 monoclonal antibody) seems to permit little placental transfer during the first trimester, but placental transfer cannot be excluded during the second or third trimester. So, the groups of women exposed to anti-TNF at the beginning of the first trimester

Infliximab for the treatment of psoriasis in Greece: 4 years of clinical experience at a single centre.

Background  Infliximab, a chimeric monoclonal antibody, has been shown to be effective for moderate to severe psoriasis. Clinical experience with long‐term infliximab therapy for psoriasis is accumulating, and it is therefore important to share our experience with its use in real‐life clinical practice.

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.