CASP8 polymorphisms contribute to cancer susceptibility: evidence from a meta-analysis of 23 publications with 55 individual studies

Abstract

Several potentially functional polymorphisms of CASP8 encoding an apoptotic enzyme, caspase 8, have been implicated in cancer risk, but individually published studies showed inconclusive results. We performed a meta-analysis of 23 publications with a total of 55 174 cancer cases and 59 336 controls from 55 individual studies. We summarized the data on the associations between three studied CASP8 polymorphisms (G>C D302H, -652 6N del and Ex14-271A>T) and cancer risk and performed subgroup analysis by ethnicity, cancer type, study design and etiology. We found that D302H CC and CG variant genotypes were associated with significantly reduced overall risk of cancers using conservative random genetic models [homozygote comparison: odds ratios (OR) = 0.79; 95% confidence interval (CI): 0.69-0.92; dominant comparison: OR = 0.93, 95% CI: 0.89-0.98; recessive comparison: OR = 0.81, 95% CI: 0.71-0.93). In further stratified analyses, the reduced cancer risk remained for subgroups of Caucasians, breast or estrogen-related cancers, and hospital- or population-based studies, except for an elevated risk for brain tumors. Similarly, the -652 6N del polymorphism was also associated with significantly reduced overall risk of cancers (homozygote comparison: OR = 0.84, 95% CI: 0.75-0.94; dominant comparison: OR = 0.88, 95% CI: 0.81-0.96; recessive comparison: OR = 0.90, 95% CI: 0.82-0.99) and all subgroups analyzed. However, the Ex14-271A>T polymorphism did not appear to have an effect on cancer risk. These results suggest that CASP8 D302H and -652 6N del polymorphisms are potential biomarkers for cancer risk.

Fig. 1.

Study flow chart for the process of selecting the final 23 publications.

Fig. 2.

ORs of overall cancer risks associated with the three most-studied CASP8 polymorphisms under the homozygote model by random effects for each of the published studies. Comparison of the minor allele homozygotes versus the common allele homozygotes. (A) G>C D302H, (B) –652 6N del and (C) Ex14-271A>T. For each study, the estimates of OR and its 95% CI were plotted with a box and a horizontal line. The symbol filled diamond indicates pooled OR and its 95% CI.

Fig. 2.

ORs of overall cancer risks associated with the three most-studied CASP8 polymorphisms under the homozygote model by random effects for each of the published studies. Comparison of the minor allele homozygotes versus the common allele homozygotes. (A) G>C D302H, (B) –652 6N del and (C) Ex14-271A>T. For each study, the estimates of OR and its 95% CI were plotted with a box and a horizontal line. The symbol filled diamond indicates pooled OR and its 95% CI.

Fig. 3.

Funnel plot analysis to detect publication bias for each of the CASP8 polymorphisms. (A) G>C D302H, (B) –652 6N del and (C) Ex14-271A>T. Each point represents an individual study for the indicated association.