Abstract
Recurrent mutations in RHOA specifically promote diffuse-type gastric cancer progression.
Major finding: Recurrent mutations in RHOA specifically promote diffuse-type gastric cancer progression.
Approach: Tumor subtype–specific driver mutations were identified using integrative genomic profiling.
Impact: Analysis of these complex genetic and epigenetic changes highlights potential therapeutic targets.
Gastric cancer can be classified into molecular and histologic subtypes, including diffuse-type gastric carcinoma (DGC), a highly infiltrative adenocarcinoma associated with poor prognosis. Although recent studies have identified several frequently mutated genes, the global genomic landscape of gastric cancer, and specifically DGC, has not been well defined. To characterize the molecular alterations in gastric cancer subtypes, Wang and colleagues performed whole-genome sequencing of 100 tumor samples as well as copy number, gene expression, and DNA methylation profiling. This integrative analysis defined distinct, tumor subtype–specific genetic and epigenetic changes, including increased promoter methylation, fewer mutations, and reduced chromosomal instability in DGCs compared with intestinal-type gastric tumors. Furthermore, in addition to known mutations in tumor-suppressor genes, mutations in genes that regulate WNT signaling, focal adhesions, and adherens junctions were enriched in gastric tumors, and frequent mutations in putative driver genes such as CTNNA2, RNF43, and MUC6 were detected. In particular, somatic mutations in RHOA were specifically identified in 14.3% of DGCs evaluated; these alterations clustered in functional domains of the RHOA small GTPase and resulted in defective signaling and resistance to anoikis. Consistent with this finding, Kakiuchi and colleagues detected recurrent nonsynonymous RHOA mutations in 25.3% of DGCs but not in intestinal-type tumors using whole-exome sequencing. These mutations, localized to the highly conserved hotspot residues Tyr42, Arg5, and Gly17, were associated with poor tumor cell differentiation and conferred a growth advantage in gastric cancer cells, suggesting a gain-of-function role for mutant RHOA in DGC progression. Together, these results underscore the complex molecular landscape in gastric cancer and suggest that RHOA is a driver gene and potential therapeutic target in DGC.