Polymorphisms of the FAS and FAS ligand genes associated with risk of cutaneous malignant melanoma

Abstract

The FAS/FAS ligand (FASLG) system has a key role in regulating cell growth and thus tumorigenesis. Functional promoter polymorphisms of the FAS and FASLG genes alter the transcriptional activities, but no published study has investigated the role of these polymorphisms in the etiology of cutaneous malignant melanoma (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, FASLG-844T>C and FASLG-IVS2nt-124G>A polymorphisms and assessed their respective associations with CMM risk. We found that an increased risk of CMM was associated with the FAS-1377GG [adjusted odds ratio (OR)=1.32; 95% confidence interval (CI)=1.00-1.75 for -1377GG] and -670AA (adjusted OR=1.28; 95% CI=1.00-1.65 for -670AA) genotypes compared to the -1377AA/AG and -670AG/GG genotypes, respectively; an increased risk of CMM was associated with the FASLG-IVS2nt-124AG+GG (OR=1.54; 95% CI=1.18-2.01) genotype compared to the AA genotype, but no evident risk was associated with any of the FAS-844T>C genotypes. In the combined analysis of these four variant alleles, we found that, compared to those having 0-3 variants, those having 4-8 variant alleles had a significantly increased risk for CMM (OR=1.38; 95% CI=1.10-1.73), and this risk was more pronounced in subgroups of old (>50 years) males, and those who were at low risk of sunlight-induced CMM, except for having fair skin colour, moles, dysplastic nevi and a family history of cancer. In conclusion, genetic variants in the FAS and FASLG genes may contribute to the etiology of CMM in the general population, particularly in those with a low risk of sunlight-induced CMM.

Association between FAS polymorphism and prostate cancer development

“…A significantly associated risk was found for FAS À670 A/G polymorphism in bladder, 13 cervical cancer, 11,16,22 cutaneous malignant melanoma, 12 esophageal and head and neck squamous cell carcinoma, 15,21 lung and nasopharyngeal cancer. 9,17,20 We analyzed the frequency of FAS genotypes in the normal control population.…”

“…7,8 In addition, polymorphisms in the FAS gene and perhaps also in the FASL gene that impair apoptotic signal transduction are associated with a high risk of cancer in various models. [9][10][11][12][13][14][15][16][17][18][19][20][21][22] Thus, the FAS/FASL system appears to have a role in the development and progression of cancer.…”

The FAS ligand promoter polymorphism, rs763110 (−844C>T), contributes to cancer susceptibility: evidence from 19 case–control studies

“…In this meta-analysis, three studies assessed the SNPs in the adjacent regions that were in linkage disequilibrium with rs763110 12,15,25 in which FASL haplotype and combined genotype analyses showed that the variant haplotypes were associated with significantly higher cancer risk. These results indicate that FASL polymorphisms may play a crucial role in the development of cancer, which is biologically plausible.…”

“…Recently, many studies have investigated the role of the FASL rs763110 in the etiology of cancers of various organs, including the breast, 13 -15 cervix, 16 -19 bladder, 20 lung, 21 -23 head and neck, 12 skin, 24,25 esophagus, 26 stomach, 27 ovary, 28 thymus, 29 and pancreas. 30 However, the results of these studies remain inconclusive.…”

Polymorphisms in the DNA Repair GenesXPC, XPD, andXPGand Risk of Cutaneous Melanoma: a Case-Control Analysis

“…All tumors of the patients were histologically classified according to the 2002 American Joint Committee on Cancer ''melanoma staging system'' (17). As previously described (15,16), cancer-free control subjects were also recruited during the same period from self-reported cancer-free visitors to M. D. Anderson Cancer Center who were not seeking medical care but instead accompanied patients to our outpatient clinics, and the response rate among those we approached for recruitment was f90%. The controls who were not blood related to the patients and agreed to donate a blood sample were frequency matched to the patients by age (F5 years), sex, and ethnicity.…”