Abstract 4719: Genome-wide association studies of pigmentation and skin cancer: A meta-analysis
Authors: Gerstenblith Meg R. , Shi Jianxin , Landi Maria Teresa 
Published: February 2011

Abstract
We performed a meta-analysis of summary results from 13 genome-wide association studies (GWAS) examining pigmentation and sun sensitivity traits, nevi, melanoma, basal cell carcinoma (BCC), and squamous cell carcinoma identified from PubMed through November 1, 2009. Two of these expanded upon findings from other GWAS and were therefore included. We grouped the significant loci from the GWAS into four categories: (1) loci associated with pigmentation (hair, eye and/or skin color), freckling, sun sensitivity traits, and skin cancer, (2) loci associated with nevi and melanoma, (3) loci associated with pigmentation and/or sun sensitivity but not skin cancer, and (4) loci distinctly associated with basal cell carcinoma (BCC) but not pigmentation, sun sensitivity, or other skin cancers. (1) GWAS confirmed the known association of SNPs in MC1R (melanocortin-1 receptor) with hair color, sun sensitivity, freckling, melanoma, and BCC. SNPs in TYR (tyrosinase), ASIP (agouti signaling protein), TYRP1 (tyrosinase-related protein 1), and SLC45A2 (solute carrier family 45, member 2) were also associated with pigmentation factors and skin cancer (melanoma and BCC for TYR and ASIP; melanoma for TYRP1; and melanoma, BCC, and squamous cell carcinoma for SLC45A2). Since three of the seven skin cancer GWAS did not adjust for pigmentation or sun sensitivity factors, we cannot conclusively separate the effects on skin cancer from the effects on pigmentation for these SNPs. (2) Two loci around the MTAP (methylthioadenosine phosphorylase) and PLA2G6 (phospholipase A2, group VI) genes were associated with nevi and melanoma. (3) The loci associated with pigmentation and/or sun sensitivity but not melanoma or BCC included four genes, namely TPCN2 (two-pore segment channel 2), KITLG (kit ligand), SLC24A4 (solute carrier family 24, member 4), and OCA2 (oculocutaneous albinism type II). IRF4 (interferon regulatory factor 4), SLC24A5 (solute carrier family 24, member 5), and HERC2 (hect domain and rcc1-like domain 2) were associated with pigmentation but not tested for skin cancers in these GWAS. (4) Finally, there were six loci distinctly associated with BCC around the following genes: PADI6 (peptidylarginine deiminase, type VI), RHOU (ras homolog gene family, member u), TERT-CLPTM1L (telomerase reverse transcriptase-CLPTM1-like protein), KLF14 (kruppel-like factor 14), CDKN2A/B (cyclin-dependent kinase inhibitor 2A/B), and KRT5 (keratin 5). Interestingly, SNPs on chromosome 16 span a region including three genes: MC1R, FANCA (fanconi anemia complementation group A), and CDK10 (cyclin-dependent kinase 10). Upon further sequencing of MC1R and adjustment for additional MC1R variants not included in the platform used in these GWAS, SNPs in CDK10 and FANCA were no longer significant. This signifies the importance of prior knowledge of melanoma risk factors (like MC1R) even in an apparent “agnostic” approach as in GWAS.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4719.