Abstract LB-335: Associations of functional polymorphisms in genes involved in the MAPK signaling pathways and cutaneous melanoma risk

Abstract

Abstract Cutaneous melanoma (CM) is the most aggressive form of skin cancers, and its incidence is increasing annually in Caucasian populations. Previous linkage studies have identified two high-penetrance genes that influence CM risk, including cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase 4 (CDK4). Recent genome-wide association studies (GWASs) on CM have successfully identified several low-penetrance loci on CM susceptibility. However, most GWASs have mainly focused on top significant single nucleotide polymorphisms (SNPs) that could reach the required genome-wide significance level, most of which did not have clear biological functions but were just surrogates for causal variants. To overcome these limitations in GWASs, several complementary approaches have been proposed recently, such as pathway-based analysis and integration analysis of association results with gene expression. These applications have successfully revealed several new cancer susceptibility genes and pathways. Thus, studying SNPs with moderate significance and putative functions in a specific pathway might be helpful to identify SNPs with a relative small effect size and provide additional insight into genetic mechanisms of cancer. Because MAPK pathways play critical roles in development and progression of CM, in this study, we reevaluated the associations between SNPs in 280 MAPK genes and melanoma risk in the discovery GWAS dataset for 1804 CM cases and 1026 cancer-free controls. We found that 34 SNPs with a significance level of 0.001. We further performed in silico prediction using SNPinfo and identified 11 SNPs with putative functions or having a high LD with functional SNPs, five of which were selected to be validated in two other GWAS datasets. A meta-analysis showed that two SNPs (rs1051849 in DUSP14 and rs4608623 near MAFF/PLA2G6) were associated with reduced CM risk (P = 0.0002 for rs1051849 and P = 0.00007 for rs4608623). Further correlation analysis of gene expression levels and SNP genotypes from 90 HapMap CEU cell lines revealed that these two SNPs had significant effects on mRNA expression of DUSP14 and MAFF, respectively (P = 0.025 for rs1051849 and P = 0.010 for rs4608623). We also performed gene-based tests using the hypergeometric method and the Versatile Gene-Based Test for Genome-wide Association (VEGAS) and found that significant SNPs were over-represented in 9 MAPK genes including DUSP14 and MAFF. Our results indicated that genetic variants in DUSP14 and MAFF might be associated with melanoma risk by influencing mRNA expression levels. Further studies are warranted to validate our findings. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-335. doi:1538-7445.AM2012-LB-335