Metastasis, making c-Met a potential therapeutic target for cancer drugs [47,48]. Interestingly, c-Met and epidermal growth factor receptor (EGFR)inhibitors can synergistically inhibit cell proliferation and promote apoptosis in lung cancer [49]. Yano et al. (2008) proposed that HGF-mediated MET Anlotinib activation can induce gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations [50]. For the rac1Pathway (Rac 1 cell motility signaling pathway), Rac-1 is a small GTP-binding protein in the Rho family that regulates cell motility and proliferation in response to extracellular signals [51]. Meanwhile, Rac-1 can function as oncogenes in fibroblasts when over expressed [52]. Rab5 can induce the activation of Rac through several mechanisms, Rab5-regulated trafficking 23977191 of Rac is involved in cell motility, which may also influence cell migration during morphogenesis and cancer metastasis [53,54]. Meanwhile, Rac activation by the IRSp53/ Eps8 complex plays an important role in the metastatic behavior of the malignant tumor cell [55]. In addition, we also checked the reported pathways by Chung et al. (2012) and Fehringer et al. (2012) in our study. Interestingly, the strongest association reported by Fehringer et al. (2012) was the acetylcholine receptor activity pathway while the achPathway was identified in the current study. Some studies have demonstrated that the activation of nicotinic acetylcholine receptors can alter apoptotic signaling as well as stimulate proliferation, both of which play an important role in lung carcinogenesis [56,57,58]. The results consistently support the importance of the 2 pathways in the development of lung cancer, which is biologically plausible. However, we did not found significant signals for other reported pathways. This may be explained by ethnic heterogeneity, SC 1 different pathway analysis methods or definition of pathways from different databases. This study has several strengths. First, we performed a two-stage pathway analysis in two independent populations, which may reduce the false-positive findings and improve the credibility of the results. Second, the four identified pathways were still stable after sensitivity analysis when considering SNP-to-gene mapping approaches and gene overlapping between pathways. This point as well as the important biology of the identified pathways in lung carcinogenesis has increased our confidence that our findings may be true other than just by chance. Nevertheless, several limitations are also need to be addressed in this study. First, incomplete annotation of human genome may reduce the study power for the pathway analysis, since many genes of unknown function cannot be assigned to known pathways and intergenic SNPs physically faraway from genes were not included yet. Thus, further studies based on improved genome-annotation database may provide additional understandings in genetics of lung cancer. Second, different pathway databases have different guidelines for pathway construction. Thus, the gene content 
of pathways representing the same biological process may vary substantially between different databases [14]. We only focused on KEGG and BioCarta databases that may have restricted our analysis due to inherent definition of the pathway, though these two databases have been commonly used in pathway analysis [19,22,24]. Finally, it’s better to perform gene-smoking interaction analysis or gene-gene interaction analysis to discuss further on the involvement o.Metastasis, making c-Met a potential therapeutic target for cancer drugs [47,48]. Interestingly, c-Met and epidermal growth factor receptor (EGFR)inhibitors can synergistically inhibit cell proliferation and promote apoptosis in lung cancer [49]. Yano et al. (2008) proposed that HGF-mediated MET activation can induce gefitinib resistance in lung adenocarcinoma with EGFR-activating mutations [50]. For the rac1Pathway (Rac 1 cell motility signaling pathway), Rac-1 is a small GTP-binding protein in the Rho family that regulates cell motility and proliferation in response to extracellular signals [51]. Meanwhile, Rac-1 can function as oncogenes in fibroblasts when over expressed [52]. Rab5 can induce the activation of Rac through several mechanisms, Rab5-regulated trafficking 23977191 of Rac is involved in cell motility, which may also influence cell migration during morphogenesis and cancer metastasis [53,54]. Meanwhile, Rac activation by the IRSp53/ Eps8 complex plays an important role in the metastatic behavior of the malignant tumor cell [55]. In addition, we also checked the reported pathways by Chung et al. (2012) and Fehringer et al. (2012) in our study. Interestingly, the strongest association reported by Fehringer et al. (2012) was the acetylcholine receptor activity pathway while the achPathway was identified in the current study. Some studies have demonstrated that the activation of nicotinic acetylcholine receptors can alter apoptotic signaling as well as stimulate proliferation, both of which play an important role in lung carcinogenesis [56,57,58]. The results consistently support the importance of the 2 pathways in the development of lung cancer, which is biologically plausible. However, we did not found significant signals for other reported pathways. This may be explained by ethnic heterogeneity, different pathway analysis methods or definition of pathways from different databases. This study has several strengths. First, we performed a two-stage pathway analysis in two independent populations, which may reduce the false-positive findings and improve the credibility of the results. Second, 
the four identified pathways were still stable after sensitivity analysis when considering SNP-to-gene mapping approaches and gene overlapping between pathways. This point as well as the important biology of the identified pathways in lung carcinogenesis has increased our confidence that our findings may be true other than just by chance. Nevertheless, several limitations are also need to be addressed in this study. First, incomplete annotation of human genome may reduce the study power for the pathway analysis, since many genes of unknown function cannot be assigned to known pathways and intergenic SNPs physically faraway from genes were not included yet. Thus, further studies based on improved genome-annotation database may provide additional understandings in genetics of lung cancer. Second, different pathway databases have different guidelines for pathway construction. Thus, the gene content of pathways representing the same biological process may vary substantially between different databases [14]. We only focused on KEGG and BioCarta databases that may have restricted our analysis due to inherent definition of the pathway, though these two databases have been commonly used in pathway analysis [19,22,24]. Finally, it’s better to perform gene-smoking interaction analysis or gene-gene interaction analysis to discuss further on the involvement o.
