Background: Sets of differentially expressed genes often contain driver genes that induce disease processes. However, various methods for identifying differentially expressed genes yield quite different results. Thus, we investigated whether this affects the identification of key players in regulatory networks derived by downstream analysis from lists of differentially expressed genes. Results: While the overlap between the sets of significant differentially expressed genes determined by DESeq, edgeR, voom and VST was only 26% in liver hepatocellular carcinoma and 28% in breast invasive carcinoma, the topologies of the regulatory networks constructed using the TFmiR webserver for the different sets of differentially expressed genes were found to be highly consistent with respect to hub-degree nodes, minimum dominating set and minimum connected dominating set. Conclusions: The findings suggest that key genes identified in regulatory networks derived by systematic analysis of differentially expressed genes may be a more robust basis for understanding diseases processes than simply inspecting the lists of differentially expressed genes