Genetic polymorphisms of FAS and FASL (CD95/CD95L) genes in cervical carcinogenesis: An analysis of haplotype and gene-gene interaction.

OBJECTIVE

Whereas human papillomavirus (HPV) infection is necessary but not sufficient for cervical carcinogenesis, host genetic variations may confer individual susceptibility. Resistance to apoptosis is a hallmark of cancer in which FAS/FAS ligand signaling plays an important role. The present study examines the hypothesis that genetic polymorphisms in FAS and FAS ligand genes, alone or in combination, are associated with cervical carcinogenesis.

METHODS

The genotypes of FAS -670A/G, FAS -1377G/A, and FASL -844C/T were assessed in 143 patients with high-grade squamous intraepithelial lesions (HSIL), 175 patients with invasive squamous cell carcinomas (SCC), and in age-matched controls by real-time PCR with allele-specific TaqMan probes. The status of cervical high-risk HPV infection was determined and adjusted to test the independence of genotype in the risk assessment.

RESULTS

The A-allele and AA-genotype frequencies of FASA -670G were significantly higher in HSIL/SCC than in controls (60% vs. 54%, P = 0.04, OR 1.26 [95% CI 1.01-1.57]; 38.0% vs. 28.6%, P = 0.02, OR 1.70 [95% CI 1.07-2.70]). No association between FAS -1377 or FASL -844 polymorphisms and HSIL/SCC could be identified. The FAS -1377A/-670A haplotype conferred a higher risk for HSIL/SCC (OR 3.05, 95% CI 1.28-7.30) than FAS -670A alone (OR 1.26, 95% CI 1.28-7.30). The interaction between FAS -670AA and FASL -844CC genotypes was associated with a risk of HSIL/SCC (OR 2.13, 95% CI 1.06-4.29) higher than that of the FAS -670AA genotype alone (OR 1.70, 95% CI 1.07-2.70).

CONCLUSIONS

The FAS -1377A/-670A haplotype in combination with FASL -844C is associated with cervical carcinogenesis.