Maintenance of genomic integrity by DNA repair genes is an essential component of normal cell homeostasis necessary to cell growth, differentiation, and apoptosis [37, 38]. Increasing evidence indicating that reduced DNA repair capacity, due to various DNA repair gene polymorphisms, is associated with increased risk and susceptibility to human solid tumors [16, 39, 40]. XPC is a key member in the NER pathway. It is involved in the recognition and initiation of the genome repair of NER pathway [10, 41, 42]. Polymorphisms in the XPC gene may alter DNA repair capacity of the NER pathway, which further play a critical role in carcinogenesis . To date, several epidemiological studies have evaluated the association between XPC Lys939Gln polymorphism and CRC risk, but the results remain inconclusive. Meta-analysis has been recognized as an important tool to more precisely define the effect of selected genetic polymorphisms on the risk for disease and to identify potential important sources of between-study heterogeneity . To derive a more precise estimation of the relationship, we performed this meta-analysis. Our meta-analysis based on 8 case–control studies suggested that the XPC Lys939Gln polymorphism contributes to increased CRC susceptibility.
In subgroup analysis by ethnicity, statistical significant increased CRC risk was detected in Asians. However, no significant association was found in Caucasians. Actually, it might not be uncommon for the same polymorphism playing different roles in cancer susceptibility among different ethnic populations, because cancer is a complicated multi-genetic disease, and different genetic backgrounds may contribute to the discrepancy. Nevertheless, owing to the limited number of relevant studies included in the meta-analysis, the observed association between XPC Lys939Gln polymorphism and CRC risk is likely to be caused by chance because study with small sample sizes may have insufficient statistical power to detect a slight effect or may have generated a fluctuated risk estimate. Currently there were only four studies on XPC Lys939Gln polymorphism and CRC risk for Asian populations, and Caucasian populations, respectively. Therefore, the observed results of our study should be interpreted with caution.
When stratified according to the quality score of the articles, statistical significant increased CRC risk was observed in high quality studies but not in low quality studies. The possible reason for the discrepancy may be that the existence of selection bias and recall bias in the low quality studies. In addition, genotyping methods without quality control in studies of low quality should be also considered when deciphering these inconsistent results. In subgroup analysis according to the source of control, statistical significant increased CRC risk was found in both population-based studies and hospital-based studies. However, the ORs and 95% CIs differ largely in these two subgroups. The reason may be that the hospital-based studies have a high risk of producing unreliable results because hospital-based controls may not always be truly representative of the general population. Therefore, a methodologically preferable design, such as using a proper and representative population-based high quality study, is of great value in case–control studies.
It is well established that the carcinogenesis of CRC is a result of the interaction between environmental factors and genetic background [18, 44]. Besides the role of genetic variants, smoking behavior shows an important effect on the CRC susceptibility. It has been reported that smoking increased CRC risk threefold . It is thought that smoking increased cancer risk due to chemicals such as hydrocarbons, arylamines, nitrosamines, and the formation of reactive oxygen species as by-products of the above compounds  that are known to induce bulky adducts, base damage, and DNA strand breaks. DNA repair mechanisms are paramount in correcting the changes on DNA and provide unmutated DNA while replication goes on . The XPC protein plays a crucial role in repairing the DNA damage caused by tobacco smoke. Individuals with the XPC variant genotype may possess deficient DNA repair capability. Accordingly, the XPC protein product may be less efficient in repairing the DNA lesions induced by tobacco smoke, and thereby could enhance the susceptibility, favoring the development of CRC. Therefore, we carried out subgroup analysis according to smoking status. Our results showed an increased CRC risk in nonsmokers but not in smokers, which was inconsistent with the hypothesis above. The results should be interpreted with caution because of the limited numbers of the original studies. Therefore, further studies concerning stratification for smoking are needed to increase power for the association estimation.
Some possible limitations in this meta-analysis should be acknowledged. First, in subgroup analysis by ethnicity, the included studies regarded only Asians and Caucasians. Data concerning other ethnicities such as Africans were not found. Thus, additional studies are warranted to evaluate the effect of this functional polymorphism on CRC risk in different ethnicities, especially in Africans. Second, our results were based on unadjusted estimates. We did not perform the analysis adjusted for other covariates such as age, drinking status, environment factors, and so on, because of the unavailable original data of the eligible studies. Third, in subgroup analyses by ethnicity, cancer location, and smoking status, the sample size of the subgroups was relatively small for stratified analyses, which may lead to relatively weak power to detect the real relationship.