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  • br Funding This work was supported by

    2019-08-13


    Funding This work was supported by the PACA Region and Avignon Université.
    Acknowledgements
    Introduction Cancer is a pivotal health problem all over the world [1]. In spite of enormous advances achieved in diagnosis and treatment over the past decades, it still accounts for over 22000 deaths every day [2]. Until now, the exact cause of cancer is still unknown. Although irregular life, smoking, heavy alcohol intake and chronic viral infection were already proved to be potential pathogenic factors of cancer by previous epidemiological investigations [3,4], the fact that a great inter-individual variability in disease susceptibility existed in these exposed to above mentioned carcinogenic factors suggested that genetic factors are also involved in cancer development. Nitric oxide (NO) is a short-lived small molecule that could exert protection effects against free radicals, but at excessive concentrations, NO or its derivatives might cause DNA damage and lead to cancer development. Therefore, balance of NO level is critical for cancer prevention [5,6]. The endothelial nitric oxide synthase (eNOS), encoded by the eNOS gene located on chromosome 7q35-36, plays a pivotal role in regulating synthesis of NO [7], and previous studies showed that eNOS may also be implicated in cancer development. Firstly, eNOS tryptophan hydroxylase levels were found to be significantly elevated in various cancerous tissues [[8], [9], [10], [11]]. Secondly, it was evident that eNOS was also involved in multiple cancer-related events such as angiogenesis, invasion and metastasis [[12], [13], [14]]. Therefore, it is biologically plausible that eNOS polymorphisms, which may alter the expression level of eNOS and impact synthesize of NO, may serve as genetic biomarkers of cancer. So far, associations between eNOS polymorphisms and individual susceptibility to cancer remain controversial. Therefore, we performed the present meta-analysis to better explore potential roles of eNOS polymorphisms in cancer development.
    Materials and methods
    Results
    Discussion To the best of our knowledge, this is so far the most comprehensive meta-analysis on associations between eNOS polymorphisms and cancer, and our pooled analyses demonstrated that rs1799983, rs2070744 and rs869109213 polymorphisms were all significantly associated with individual susceptibility to cancer. Further subgroup analyses revealed that rs2070744 and rs869109213 polymorphisms were only significantly associated with individual susceptibility to cancer in Caucasians, whereas the rs1799983 polymorphism was significantly associated with individual susceptibility to cancer in both Caucasians and Asians. There are several points that need to be addressed about this meta-analysis. Firstly, previous experimental studies showed that mutant alleles of investigated polymorphisms were all correlated with reduced eNOS activity and decreased NO generation, which may partially explain our positive findings [60,61]. Secondly, the pathogenic mechanism of cancer is highly complex, and hence it is unlikely that a single gene polymorphism could significantly contribute to its development. As a result, to better illustrate potential correlations of certain gene polymorphisms with cancer, we strongly recommend further studies to perform haplotype analyses and explore potential gene-gene interactions. Thirdly, it is worth noting that Haque et al. also tried to analyze the effects of eNOS polymorphisms on cancer development through a meta-analysis in 2015, and significant associations with cancer were only detected for rs2070744 polymorphism in overall population [62]. Compared with this previous study, 10 more studies about rs869109213 polymorphism, 8 more studies about rs2070744 polymorphism, and 8 more studies about rs1799983 polymorphism were enrolled for analyses in our current meta-analysis. Therefore, our pooled findings should be considered as more conclusive. However, it is also notable that the sample sizes of several subgroup comparisons were still relatively small, and thus may be statistically inadequate to detect the actual relationship between eNOS polymorphisms and certain types of cancer. Thus, further studies with larger sample sizes are still needed to confirm our findings.