Comprehensive field synopsis and systematic meta-analyses of genetic association studies in cutaneous melanoma

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.

Figure 1

Overview of the literature search and selection strategy of published genetic association studies of cutaneous melanoma. A) An initial PubMed search for “melanoma AND associat* AND gene*” was performed to identify articles published on or before March 31, 2009. Screening of those as well as of cross-references in relevant articles and additional search of the Human Genome and Epidemiology Network Navigator (25) and the Melanoma Molecular Maps Project (26) databases identified publications that fulfilled our inclusion criteria. B) Following the initial screening, daily PubMed searches for “melanoma AND associat* AND gene*” were performed to identify additional articles published before July 31, 2010 (the data freeze). C) The publication search continued after the date of the data freeze and yielded four additional articles until October 14, 2010. Data from articles of this period have not been included in the meta-analyses of the current article but are included in the online database. Asterisks indicate that the number of nominally statistically significant and non-statistically significant genes does not sum to the total number of genes because genes encoding cyclin-dependent kinase 2A, the melanocortin-1 receptor, and the vitamin D receptor contained polymorphisms showing both statistically significant (P < .05) and non-statistically significant genetic variants identified by meta-analysis.