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    • N6022 br Materials and Methods br Results br

    2018-11-01


    Materials and Methods
    Results
    Discussion Tumors of the urinary system were reported to make significant threaten to the overall human cancer burden (Parkin, 2008). A wide variable incidence of urological neoplasms indicates its multi-factorial aetiology that involves the interactions between genetic and ethnic backgrounds, as well as the environmental factors. In human beings, XRCC genes that are relevant to DNA repair and damage prevention pathways are critical for preventing cancer initiation and progression. The XRCC1, situated at chromosome 19q13.3, can produce XRCC1 enzyme that involved in BER pathway. It may be particularly important for urological neoplasms, functioning as repairing uracil and oxidative DNA damage (Taylor et al., 2002). The XRCC2 protein encoded by the XRCC2 genes, one of homologue of the RecA protein, displaces replication protein A (RPA) on the exposed single-stranded DNA, which takes responsibility for repairing the DNA double-strand breaks (DBS) (Riha et al., 2006). Similarly, the XRCC3 protein is involved in the homologous recombination repair (HR) pathway and the XRCC4, XRCC7 protein in the non-homologous end joining (NHEJ), also responsible for repairing DBS. It is hypothesized that polymorphisms in XRCC genes of BER, NER, DSBR and MMR pathways may be important risk factors for the development of urological neoplasms. Some investigators have conducted case-control studies to evaluate the association between polymorphisms in XRCC genes and the risk of urological tumors. However, most of former studies stressed on limited polymorphisms in XRCC genes while neglected potential multiple genes\' influence on carcinogenesis. In current study, we presented a comprehensive meta-analysis and systematic review for five DNA repair genes (XRCC1, XRCC2, XRCC3, XRCC4 and XRCC7) to examine the association between these polymorphisms and the risk of urological neoplasms. Overall, our findings suggested that XRCC1-rs25489 polymorphism was associated with an increased risk of urological neoplasms in heterozygote and N6022 models, a result consistent with Mittal et al.\'s (2012b) work. However, in the research conducted by Zhu et al. (2014), they did not uncover a significant association between XRCC1 polymorphisms and urological neoplasms risk. In further subgroup analyses categorized by cancer type, XRCC1-rs25489 polymorphism was identified as a risk factor for BC in heterozygote model. In addition, significantly increased risk of urological neoplasms in Asians was also identified for XRCC1-rs25487 polymorphism in allelic and homozygote models, while no significant association was revealed for the overall, a result consistent with previous study conducted by Fontana et al. (2008). Furthermore, we also performed LD analysis to find the potential LD association between the two significant risk factors in XRCC1 (rs25487 and rs25489), however, an extremely lower LD was identified for them in all the four commonly researched populations (r2<0.10). Moreover, subgroup analysis based on source of controls suggests a significant association between XRCC1-1799782 polymorphism and the risk of urological neoplasms in homozygote model for hospital-based group. The existence of this phenomenon may be due to the inconsistencies in control groups. Although majority of the controls were selected from healthy populations, many individuals may have suffered from other non-cancer diseases. While for other polymorphisms, no significant association was found. It is worth noting that our data for XRCC3-rs861539 was not consistent with several previously published studies. In the study performed by Shen et al. (2003), they found that the XRCC3 rs861539 variant genotype exhibited a protective effect against BC (OR=0.63; 95% CI=0.42–0.93), which was further validated by Narter et al. (2009). On the contrary, Zhu et al. (2012) genotyped a comprehensive case-control studies of 150 BC cases and 150 controls and identified an elevated BC risk among individuals who carry at least one mutated variant allele (OR=3.22, 95% CI=1.14–9.11, P=0.030), and similar results was also obtained by Andrew et al. (2007) Moreover, the frequency of XRCC3-rs861539 genotype distributions in some of the control groups were departed from HWE and thus we cannot rule out the possibility that such an association occurred as a result of bias. Then, we conducted a subgroup analysis by HWE status, and identified that HWE status did not give rise to the bias of results. In addition, the stability of meta-results was further enhanced by sensitivity analysis.