The Fas/Fas ligand (FasL) system has a key role in regulating cell growth, and thus tumorigenesis, in cutaneous malignant melanoma (CMM). Functional promoter polymorphisms of the Fas and FasL genes may alter their transcriptional activities, but no published study has investigated the role of genetic polymorphisms of the Fas and FasL genes in the etiology of CMM. We hypothesized that Fas and FasL polymorphisms are associated with risk of CMM. In a hospital-based case-control study of 602 non-Hispanic white CMM patients and 603 cancer-free age- and sex-matched control subjects, we genotyped Fas -1377G>A, Fas -670A>G, FasL -844T>C, and FasL IVS2nt-124G>A polymorphisms and assessed their associations with CMM risk. The Fas -1377GG and -670AA genotypes were associated with an increased risk of CMM compared with the -1377AA/AG and -670AG/GG genotypes, respectively (adjusted odds ratio [OR], 1.32; 95% CI, 1.00-1.75 for -1377GG and adjusted OR, 1.28; 95% CI, 1.00-1.65 for -670AA). Compared with the FasL IVS2nt-124AA genotype, an increased risk of CMM was associated with the FasL IVS2nt-124AG (OR, 1.55; 95% CI, 1.18-2.04) and AG+GG (OR, 1.54; 95% CI, 1.18-2.01) genotypes. Furthermore, the risk of CMM increased as the numbers of both Fas (i.e., -1377G and -670A; Ptrend = 0.021) and FasL (-844C and IVS2nt-124A; Ptrend = 0.007) variants increased. In the combined analysis of these four variants, we found that the increased risk was associated with the genotype that had 4-8 variant alleles (OR, 1.38; 95% CI, 1.10-1.73) compared with the genotype that had 0-3 variants. In conclusion, genetic variants in the Fas and FasL genes may jointly contribute to the etiology of CMM. (Supported in part by National Institutes of Health grants R01 CA100264, P50 CA093459, R01 ES11740, U01 ES11047, and P30 CA16672)

[Proc Amer Assoc Cancer Res, Volume 47, 2006]