In the present meta-analysis, we examined the association between two widely studied CYP2E1 polymorphisms (PstI/RsaI, DraI) and head and neck cancer risk. We found that the variant homozygote of the CYP2E1 PstI/RsaI polymorphism was significantly associated with cancer risk in the overall comparisons, compared with the wild homozygote. We also observed a significant association between the CYP2E1 DraI polymorphism and cancer risk for homozygote in the overall comparisons.
As for the PstI/RsaI polymorphism of CYP2E1, our result showed a significantly high cancer risk for the c2 homozygote in Asian populations, with no such association being found among Caucasian population under any of the three genetic models. Ethnic differences may attribute to these different results, since the distributions of the less common c2 allele were different between various races, with a prevalence of ~25-50% and 5-10% among Asians and Caucasians, respectively . The c2 variant allele frequency did reach a statistically significant level among Asians, while in the Caucasian populations, the lack of significant association might be explained by the substantially lower statistical power caused by the lower prevalence of CYP2E1 c2 allele (5-10% against 25-50% for Asians).
CYP2E1 is presumed to confer susceptibility to HNSCC by metabolizing carcinogens but, unfortunately, few of the studies explored the interaction between the CYP2E1 genotype and smoking habits or alcohol consumption. This may be due to the low statistical power of the individual studies to detect such interactions; but all the studies which collected these data were utilized for this meta-analysis. The stratified meta-analyses of all the data on the PstI/RsaI genotype and smoking habits or alcohol consumption with respect to head and neck cancer risk produced no statistically significant results. These results suggest that when the environmental and genetic risk factors are both present, the combined effect on head and neck cancer seems to be no longer than additive of the separate effects. However, we cannot ignore the fact that owing to the low prevalence of c2 homozygotes in each study, even when data are pooled, the statistical power to detect an interaction remains low.
In addition, the DraI polymorphism was associated with an increased cancer risk among Asians but not among Caucasians, suggesting an ethnic difference in terms of genetic and environmental factors . However, only two studies of the DraI polymorphisms used Asian population data and it is therefore probable that the observed ethnic differences were simply due to chance, given that studies with small sample size may have insufficient statistical power to detect a slight effect. Additional studies are therefore required to further validate ethnic differences in the effect of DraI polymorphisms on cancer risk, especially in Asian populations.
Currently, the mechanism whereby the rare allele of the RsaI/PstI and DraI polymorphisms increases the risk of head and neck cancer risk are still not clear. CYP2E1 is a phase I enzyme, which plays an essential role in the metabolic activation of low molecular weight compounds and pro-carcinogens such as N-nitrosamines, benzene, and halogenated hydrocarbons. There is strong evidence from in vitro studies suggesting that the rare allele of the RsaI/PstI polymorphisms in the CYP2E1 gene probably confers a higher risk of HNSCC susceptibility by increasing transcriptional and enzyme activity . Thus, the c2/c2 genotypes may be more liable to metabolically activate mutagens and carcinogens. As for the rare allele of the DraI polymorphism of the CYP2E1 gene, in vitro expression studies indicate that it is associated with increased transcriptional activity . The AA genotypes may therefore have more ability to metabolize mutagens and pro-carcinogens.
Some limitations should be considered when interpreting our results, in addition to those inherited from the meta-analysis. First, our results are based on unadjusted estimates, whereas adjustments for factors such as age and sex would produce a more precise analysis. The lack of this kind of information may cause serious confounding bias. Further large and well-designed studies need to be performed to further confirm all these results. Secondly, the subgroup meta-analyses dealing with interactions between the CYP2E1 genotype and smoking habits/alcohol consumption are based on the small number of studies where such information is available. Nevertheless the number of subjects included in this part of the analysis comprised the largest sample of all. Third, the quality score of the individual studies included in our meta-analysis was assessed on the basis of trying to minimize the potential for selection bias, misclassification related to exposure, collection of data on potential confounders and method of statistical analysis. No validated quality assessment system currently exists, and it is evident that our quality scale has a subjective component.