2.1 Search results
A total of 1047 articles were searched:9 from CBM, 158 from Embase, 251 from PubMed, 194 from Web of science,130 from Wanfang date, 32 from Veep and 273 from CNKI. After carefully inspection of these articles, 12 Original studies7, 11-21 were finally enrolled in our meta-analysis. The detail processes of study selection were showed in the flow diagram (Fig. 1). The clinical features and NOS scores of the included studies were shown in Table 1. In the end, 4790 patients (1752 STAS positive patients and 3038 STAS negative patients) were included in the analysis. The overall quality of the included literatures was high, with NOS scores above 6 stars.
2.2 Results of Meta-analysis
2.2.1 The association between EGFR genotype and STAS in lung adenocarcinoma
A total of 11 original studies were included 11-21. We combined these studies using random effects. In the original studies, 3 studies suggested no significant association between EGFR expression and STAS, 1 study suggested that patients with EGFR mutation had a higher risk of STAS positivity, and 7 studies suggested that patients with EGFR mutation had a lower probability of STAS positivity. This meta-analysis showed that among patients with lung adenocarcinoma, patients with mutant EGFR had a lower probability of STAS(RR=0.75,95%CI 0.63~0.90 z=3.09 P=0.002 Fig. 2).
2.2.2 The association between KRAS genotype and STAS in lung adenocarcinoma
A total of 4 original studies were included 11, 12, 14, 17. We combined these studies using fixed effects. In these original studies, all of the 3 papers believed that KRAS was not associated with STAS within the confidence interval of P >0.1. However, the results of this meta-analysis suggested that patients with KRAS gene mutation had a higher incidence of STAS(RR=1.17 95%CI 1.00~1.37 z=1.99 P=0.047 Fig. 3). This may be related to the relatively low proportion of patients with KRAS mutation. If the sample size can be expanded, we believe that the original study will also get the same results as this meta-analysis.
2.2.3 The association between BRAF genotype and STAS in lung adenocarcinoma
A total of 2 original studies were included 14, 17. We combined these studies using random effects. Meta-analysis results showed that BRAF mutation patients had a significantly increased incidence of STAS(RR=2.12 95%CI 1.17~3.84 z=2.47 p=0.013 Fig. 4)。
2.2.4 The association between ALK genotype and STAS in lung adenocarcinoma
A total of 7 original studies were included 7, 11, 12, 14-16, 21. We combined these studies using random effects. Meta-analysis results showed that patients with ALK gene mutation had a higher incidence of STAS than patients with ALK wild type.(RR=2.03 95%CI 1.56~2.66 z=5.21 p<0.001 Fig. 5.1)However, during the merger process, we found that the heterogeneity could be eliminated only by eliminating the results of Zhang, Z. 16. After the exclusion of Zhang's study, we combined using fixed effect, and still concluded that patients with ALK gene mutation had a higher probability of STAS. (RR=1.71 95%CI 1.53~1.90 z=9.74 p<0.001 Fig. 5.2)
2.2.5 The association between PD-L1 genotype and STAS in lung adenocarcinoma
A total of 3 original studies were included 13, 14, 18. We combined these studies using fixed effects. In the original study, HU, S Y’s study14 believed that among lung adenocarcinoma patients, the probability of PD-L1 mutation patients developing STAS was significantly lower than that of PD-L1 wild-type patients. However, the results of this meta-analysis indicated that there was no significant correlation between PD-L1 and the incidence of STAS in lung adenocarcinoma patients. (RR=1.07 95%CI 0.83~1.37 z=0.52 p=0.602 Fig. 6)
2.2.6 The association between ROS1 genotype and STAS in lung adenocarcinoma
A total of 4 original studies were included 11, 12, 15, 16. We combined these studies using fixed effects. In the original study, three studies suggested that patients with ROS1 gene mutation had a higher incidence of STAS11, 12, 15. The combined results of this meta-analysis showed that patients with ROS1 gene mutation had a higher incidence of STAS(RR=1.57 95%CI 1.35~1.82 z=5.80 p<0.001 Fig. 7)
2.3 Sensitivity analysis and publication bias
Begg’s funnel plot and Egger’s linear regression test were used to study the publication offset of the included studies with the combined number of literatures greater than or equal to 4. All content within a confidence interval of P>0.1 can be considered to have no publication offset (Table. 2). In this analysis, it was found that the research conclusions of Zhang, Z. 16 on the relationship between ALK and STAS occurrence were greatly deviated from other studies, which had a great impact on the results of data merging.(Fig .8) Therefore, the heterogeneity could be eliminated if this paper was excluded. However, whether this study is excluded or not, it can be concluded that patients with ALK gene mutation have a higher incidence of STAS. We believe that the heterogeneity may be related to the selection of reagents。