Meta-analysis Of XPC Polymorphisms And Cancer Risk And Study On Risk Factors Of Early Biological Effects For Polycyclic Aromatic Hydrocarbons Exposure

Objective Many host factors or biomarkers are involved in the process of early DNA damage induced by environmental exposure to polycyclic aromatic hydrocarbons (PAH). This study intends to explore a reasonable risk assessment mode which can identify risk factors of DNA damage or cancers, and further reveal the complicated interrelationship among those risk factors.Methods1. We conducted searches on PubMed database and EMBASE database, last search update March 2008, with these keywords"XPC"and"cancer", and totally 27 papers for were retrieved and included in this meta-analysis of the three polymorphisms of XPC (Lys⁹³⁹Gln, PAT+/-, and Ala⁴⁹⁹Val) and tobacco-related cancers.2. In this study, we included 235 subjects (166 coke-oven workers and 69 non-exposed controls) whose data on the comet assay (e.g. Olive tail moment) and cytogenetic analysis of peripheral blood lymphocytes as well as urinary 1-hydroxypyrene (1-OHP) were available. Path analysis and back-propagation neural network (BPNN) were employed to identify the risk factors. In neural network analysis, the mean impact value (MIV) was calculated for the comparisons of different risk factors.Results1. We found an increased overall cancer risk for variant homozygotes of Lys⁹³⁹Gln (OR = 1.16, 95% CI, 1.05-1.28) and Ala⁴⁹⁹Val (OR = 1.24, 95% CI, 1.08-1.42) compared with their corresponding wild-type homozygotes. When stratified by cancer type, the variant Gln939 homozygous genotype was a risk factor for lung cancer (OR = 1.28, 95% CI, 1.07-1.53), whereas the Val499 variant homozygous genotype was a risk factor for bladder cancer (OR = 1.33, 95% CI, 1.06-1.68) compared with their corresponding wild-type homozygous genotypes. For the XPC-PAT polymorphism, we found a decreased cancer risk associated with the PAT+/- genotype only in Asians compared with the PAT-/- genotype. Five studies were pooled for stratification analysis to explore the gene-smoking interaction. And there was a joint effect between PAT +/+ and smoking in cancer risk.2. The path analysis showed that coke-oven exposure and tobacco smoke were both significant predictors of the concentrations of urinary 1-OHP (P < 0.05), with a coefficient of determination of 0.75. The factors having significant influence on the Olive tail moment were in the following order: urinary 1-OHP > XRCC1-exon9 variant genotype > ERCC2-exon10 variant genotype > XRCC1-exon6 variant genotype with a coefficient of determination of 0.22. The variables of relative importance in influencing on cytokinesis-block micronucleus frequencies were in the following order: coke-oven exposure > urinary 1-OHP > age > mEH3 variant genotype > ERCC2-exon10 variant genotype > XRCC1-exon6 variant genotype with a coefficient of determination of 0.27.3. The final BP network structure was 17-8-1. The sequence of MIV for the main risk factors of CBMN was as follows: coke-oven exposure, mEH3 variant genotype, ERCC2-exon10 variant genotype, XRCC1-exon10 variant genotype, and smoke. And the effect of mEH3 genotype on CBMN was negative.Conclusion The meta-analyses suggested that XPC Lys⁹³⁹Gln, PAT+/-, and Ala⁴⁹⁹Val were likely to be determinants of susceptibility to cancers. However, a single larger study with subjects of the same ethnic background and tissue-specific biochemical and biological characterization was warranted to validate these preliminary results. The results of path analysis indicated that exogenous agents, especially the coke-oven exposure, played a more important role than the genotypes in the induction of early genetic damage. In conclusion, the path analysis and neural network appeared to be an alternative statistical approach for the ascertainment of complicated association among related biomarkers for the assessment of occupational exposure.