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

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

1. Foteini Chatzinasiou,
2. Christina M. Lill,
3. Katerina Kypreou,
4. Irene Stefanaki,
5. Vasiliki Nicolaou,
6. George Spyrou,
7. Evangelos Evangelou,
8. Johannes T. Roehr,
9. Elizabeth Kodela,
10. Andreas Katsambas,
11. Hensin Tsao,
12. John P.A. Ioannidis,
13. Lars Bertram and
14. Alexander J. Stratigos

+ Author Affiliations

1.
Affiliations of authors: Department of Dermatology, University of Athens, Andreas Sygros Hospital, Athens, Greece (FC, KK, IS, VN, EK, AK, AJS); Neuropsychiatric Genetics Group, Department of Vertebrate Genomics, Max Planck Institute for Molecular Genetics, Berlin, Germany (CML, JTR, LB); Department of Neurology, Johannes Gutenberg University, Mainz, Germany (CML); Biomedical Informatics Unit, Biomedical Research Foundation of the Academy of Athens, Athens, Greece (GS); Clinical and Molecular Epidemiology Unit, Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece (EE, JPAI); Department of Mathematics and Computer Science, Free University Berlin, Berlin, Germany (JTR); Department of Dermatology, Wellman Laboratories of Photomedicine, Massachusetts General Hospital, Boston, MA (HT); Stanford Prevention Research Center, Department of Medicine and Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA (JPAI); Center for Genetic Epidemiology and Modeling, ICRHPS, Department of Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, MA (JPAI)

1. Correspondence to:
Alexander J. Stratigos, MD, Department of Dermatology, University of Athens Medical School, Andreas Sygros Hospital, Dragoumi 5, Athens 161 21, Greece (e-mail: alstrat@hol.gr).

* Received November 21, 2010.
* Revision received May 3, 2011.
* Accepted May 5, 2011.

Abstract

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.

* © The Author 2011. Published by Oxford University Press.

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