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Updated: Apr 30, 2026
RhoC GTPase Activation Assay
Published on: August 22, 2010
Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma
Miwako Kakiuchi1, Takashi Nishizawa2, Hiroki Ueda3
11] Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan. [2] Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.
Abstract:
Diffuse-type gastric carcinoma (DGC) is characterized by a highly malignant phenotype with prominent infiltration and stromal induction. We performed whole-exome sequencing on 30 DGC cases and found recurrent RHOA nonsynonymous mutations. With validation sequencing of an additional 57 cases, RHOA mutation was observed in 25.3% (22/87) of DGCs, with mutational hotspots affecting the Tyr42, Arg5 and Gly17 residues in RHOA protein. These positions are highly conserved among RHO family members, and Tyr42 and Arg5 are located outside the guanine nucleotide-binding pocket. Several lines of functional evidence indicated that mutant RHOA works in a gain-of-function manner. Comparison of mutational profiles for the major gastric cancer subtypes showed that RHOA mutations occur specifically in DGCs, the majority of which were histopathologically characterized by the presence of poorly differentiated adenocarcinomas together with more differentiated components in the gastric mucosa. Our findings identify a potential therapeutic target for this poor-prognosis subtype of gastric cancer with no available molecularly targeted drugs.
Insights
Researchers discovered recurrent RHOA mutations in diffuse-type gastric cancer (DGC), a highly malignant form of stomach cancer. These specific RHOA mutations may represent a novel therapeutic target for DGC patients.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Diffuse-type gastric carcinoma (DGC) exhibits aggressive behavior with significant infiltration and stromal response.
- Current therapeutic options for DGC are limited, especially for this poor-prognosis subtype.
Purpose of the Study:
- To investigate the genetic landscape of diffuse-type gastric carcinoma.
- To identify potential molecular targets for DGC treatment.
Main Methods:
- Whole-exome sequencing was performed on 30 DGC cases.
- Validation sequencing was conducted on an additional 57 DGC cases.
- Functional assays were used to assess the impact of identified mutations.
Main Results:
- Recurrent nonsynonymous mutations in the RHOA gene were identified in 25.3% of DGC cases (22/87).
- Mutational hotspots were observed at Tyr42, Arg5, and Gly17 residues of the RHOA protein.
- Functional evidence suggests a gain-of-function mechanism for mutant RHOA.
- RHOA mutations were found to be specific to DGC, distinguishing it from other gastric cancer subtypes.
Conclusions:
- RHOA mutations are a significant genetic alteration in diffuse-type gastric cancer.
- Mutant RHOA may play a role in the pathogenesis of DGC.
- RHOA presents a potential therapeutic target for DGC, a subtype lacking targeted therapies.
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