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

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 This meta-analysis combines 11 GWAS (5 previously unpublished) and a further three stage 2 data sets, totaling 15,990 CMM cases and 26,409 controls.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.[Please see the Supplementary Note for acknowledgments.]This is the author accepted manuscript. The final version is available from NPG via http://dx.doi.org/10.1038/ng.337

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 &gt;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&lt;5 x 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 x 10-8 &lt;P&lt;1 x 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

CDKN2A/CDK4 Status in Greek Patients with Familial Melanoma and Association with Clinico-epidemiological Parameters

Approximately 5–10% of melanoma cases occur in a familial context. CDKN2A/CDK4 were the first high-penetrance melanoma genes identified. The aims of this study were to evaluate CDKN2A/CDK4 variants in Greek familial melanoma patients and to correlate the mutational status with specific clinico-epidemiological characteristics. A cross-sectional study was conducted by genotyping CDKN2A/CDK4 variants and selected MC1R polymorphisms in 52 melanoma-prone families. Descriptive statistics were calculated and comparisons were made using the χ2 test, Fisher’s exact test and Student’s t-test for statistical analysis, as appropriate. CDKN2A variants were detected in 46.2% of melanoma-prone families, while a CDK4 variant was found in only one family. This study confirmed that, in the Greek population, the age at melanoma diagnosis was lower in patients carrying a variant in CDKN2A compared with wild-type patients. No statistically significant associations were found between CDKN2A mutational status and MC1R polymorphisms

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 &lt; .05) of which four loci showed a genome-wide statistically significant association (P &lt; 1 x 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

Replication and Predictive Value of SNPs Associated with Melanoma and Pigmentation Traits in a Southern European Case-Control Study

<div><h3>Background</h3><p>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.</p> <h3>Methods</h3><p>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.</p> <h3>Results</h3><p>Risk allele frequencies were significantly lower compared to the HapMap CEU for eight SNPs (rs16891982 – <em>SLC45A2</em>, rs12203592 – <em>IRF4</em>, rs258322 – <em>CDK10</em>, rs1805007 – <em>MC1R</em>, rs1805008 - <em>MC1R</em>, rs910873 - <em>PIGU</em>, rs17305573- <em>PIGU</em>, and rs1885120 - <em>MTAP</em>) and higher for one SNP (rs6001027 – <em>PLA2G6</em>) 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 <em>CLPTM1L</em> (odds ratio [OR] 1.60, 95% CI 1.22–2.10; P = 0.001), rs16891982-C in <em>SCL45A2</em> (OR 0.51, 95% CI 0.34–0.76; P = 0.001), and rs1805007-T in <em>MC1R</em> (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 <em>CDK10</em>, rs1805005-T in <em>MC1R</em>, rs1885120-C in <em>MYH7B</em>, rs2218220-T in <em>MTAP</em> and rs4911442-G in the <em>ASIP</em> 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).</p> <h3>Conclusion</h3><p>Overall, our study has validated genetic variants that are likely to contribute to melanoma susceptibility in the Greek population.</p> </div

Correlation of effect sizes.

<p>Correlation of the effect sizes found in the Greek population and those described in the original publication or MelGene..Not shown are: rs4636294 (excluded from analyses because of HWE deviation); rs1011970 because OR was not available in the original publication and/or MelGene; rs1805009 and rs11547464 because all subjects were homozygous for the major allleles.</p

Areas under the curve (AUC) for 3 predictive models.

<p>Receiver operating characteristic curves for the 3 models including respectively the non-genetic risk factors alone, the non-genetic risk factors with the 3 SNPs surviving Bonferoni correction, and the non-genetic risk factors with all 8 nominally significant SNPs.</p

Results of the univariable and multivariable analyses adjusting for hair color, skin color, eye color, phototype, sunburn and tanning and comparison with data from MelGene [23].

1<p>Association analysis on negative strand.</p><p>Abbreviations: NS, not significant.</p>2<p>MelGene status = Data from MelGene, an online database of reported genetic associations of melanoma including a systematic meta-analysis of melanoma-associated variants from published datasets and grading of these associations for strength of epidemiogical evidence <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055712#pone.0055712-Chatzinasiou1" target="_blank">[23]</a>. OR (95% CI) and p value correspond to nominal association with melanoma after meta-analysis of data for each variant.</p>3<p>For this variant no meta-analysis was performed in MelGene due to the lack of sufficient datasets. The data represent those derived from the initial GWAS reporting an association of this variant with melanoma <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0055712#pone.0055712-Nan2" target="_blank">[50]</a>.</p

Correlation of risk allele frequencies.

<p>Correlation of the risk allele frequencies found in the Greek population and the frequencies of the same alleles from the HapMap CEU sample. Not shown are: rs4636294 (excluded from analyses because of HWE deviation); rs1805009 and rs11547464 because all subjects were homozygous for the respective major alleles and OR and hence risk allele could not be identified.</p