Comprehensive molecular characterization of Rho GTPases and their regulators across human cancers

Although defects in Rho GTPases have been implicated in cancer, a systematic assessment of the alterations in Rho GTPases and their regulators that facilitate conformational cycling between the active GTP-bound and inactive GDP-bound Rho GTPases is lacking across human cancers. Here, we depicted a comprehensive molecular characterization of 169 genes encoding Rho GTPases and their regulators, utilizing multi-omics data of 9125 tumor samples across 33 cancer types from The Cancer Genome Atlas. Relevant findings were consolidated using mRNA expression profiles from 10,107 samples spanning seven distinct cancer types, along with data from multiple hepatocellular carcinoma (HCC) cohorts comprising 673 patients. We identified 19 candidate driver genes characterized by significant non-silent somatic mutation patterns. Rho GTPase and its regulator genes exhibited widespread dysregulation across various cancer types, mediated by diverse mechanisms, including miRNA regulation, methylation patterns, and copy number alterations, which was significantly associated with patient overall survival. Notably, we found SYDE2 was significantly associated with poorer survival outcomes in KIRC, negatively regulated by miRNA-142-5p, with both exhibiting significant differential expression. Unsupervised consensus clustering was performed to identify common Rho GTPase regulation subtypes across human cancers; six subtypes were identified, with each exhibiting different associations with patient outcomes. Using HCC as an example, we found Cluster 6-like tumors consistently exhibited aggressive characteristics, characterized by mutated TP53 and abnormal energy metabolism. Our study underscores the importance of Rho GTPases and their regulators in cancer development and establishes a foundation for the development of therapeutic targets based on Rho GTPase signaling.