Associations between the Genetic Polymorphisms of Osteopontin Promoter and Susceptibility to Cancer in Chinese Population: A Meta-Analysis

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Discussion

Osteopontin is a member of small intrgrin-binding ligand N-linked glycoproteins (SIBLINGs) family. There are many pieces of evidences indicating that osteopontin profoundly regulate the development and progression of various tumors. Additionally, OPN expression was significantly higher in human cancers tissues than in matched normal tissues and it was significantly associated with nodal metastasis and more advanced clinical stage. Therefore, numerous publications have tested OPN as a biomarker for cancer invasiveness [31–34]. However, the associations with tumorigenesis have not been proved well. Polymorphisms in the OPN gene, SPP1, may potentially alter the expression of OPN and then modulate the risk for cancer. In recent years, SNPs have been identified as a powerful tool for predicting some complex diseases. However, previous genetic epidemiological studies about the associations between OPN gene polymorphisms and the risk of human cancer are limited, and the results were inconclusive. To our knowledge, this is the first meta-analysis which investigated the possible correlations of rs11730582 (-443 T>C), rs17524488 (-156G>GG), and rs28357094 (-66T>G) polymorphisms in the SPP1 gene with cancer susceptibility.
Our results revealed that -443T>C polymorphism might have no relation with pathogenesis of cancer. And we found that different studies had inconsistent results about this polymorphism even for the same cancer. For example, Chen JX [22] said that in a recessive genetic model TC + CC genotypes significantly decrease the risk of glioma when compared with TT, but Shen ZP [26] considered that the glioma patients had markedly high frequency of -443CC genotype than controls. Another two studies [29,30] showed that there was no significant difference in the distribution of -443 between cancer patients and controls. What’s more, large heterogeneity was found in four gene models (P<0.0001). Previous meta-analysis about human cancer risk found that the cancer type might contribute most to the source of heterogeneity [35,36]. In this study, the subgroup analysis on basis of cancer types was not calculated because of the limited number of studies. So this result should be interpreted with caution.
For -156G>GG, our study found that GG allele was at significant high risk for cancer under all four genetic models, and this result was confirmed among studies in HWE. When we exclude the study of Mu GY [25] which may be source of the heterogeneity, the results remain unchanged. That means the SNP of -156G>GG may considerably act a potential candidate of biomarker for cancer risk.
The meta-analysis of -66T>G include eight studies, however, two studies [24,29] that was not estimable in meta-analysis (Fig 2). The results of polymorphism in a dominant model showed that the genotypes TG+ GG significantly decreased the risk of cancer when compared with TT. Noteworthy, the association was disappear when exclude the study of Xu Q [27] that may be the source of the heterogeneity. So, the result is instable and further studies are necessary to clarify the association.
High OPN expression in the primary tumors is associated with cancer risk, metastasis and poor clinical outcome [37–39]. The previous study showed that -443 promoter region exerts influence on OPN gene expression in melanoma cells [40]. In our including studies, four studies [10,25,26,28] observed the association of OPN levels and SPP1 polymorphisms. Mu GY [25] and Zhang R [28] observed that the high OPN expression was more frequent in samples from -443 CC carriers than TT carriers, However, Shen ZP [26] found that none of the polymorphisms affected the serum OPN levels, Wang JL [10] thought that carriers of CC and CT genotype of -443 presented lower serum osteopontin levels than those of TT genotype. Among the four studies only two gave the accurate data, so we cannot offer further statistics. The result may be caused by following reasons: (1) the SPP1 polymorphisms affected the tumor OPN expression level, but not the serum OPN level; (2) the association is indeed related and further studies are just needed; (3) SPP1 polymorphisms make no difference in OPN level.
Some advantage could be highlighted in this meta-analysis. On one hand, this research shed lights on the relationship of genetic polymorphisms in SPP1 gene and the increased susceptibility to human cancers in Chinese population systematically. One the other hand, the exhaustive inclusion criteria and articles on wide range of cancers enhanced the power and persuasion of our conclusion. Furthermore, all literatures included had acceptable quality scores (scored at least 6). Meanwhile, we were also aware of several limitations of our study. First, all eligible studies come from China and the patients are Chinese population. Second, the number of the studies, especially for -66T>G polymorphism, was not sufficiently large, Third, for -443T>C polymorphism, the heterogeneity was big, the comprehensive analysis should be explain with caution.

Conclusion

This meta-analysis suggests that in Chinese population the -156G>GG polymorphism of SPP1 might be a risk factor for human cancers, while -443T>C mutation is not associated with cancer risk. For -66T>G polymorphism, it may be a protective factor for human cancers.