Abstract
BackgroundRecent studies have discovered recurrent RHOA mutations in diffuse-type gastric cancers. These reports show mutant RhoA is an important cancer driver and is a potential therapeutic target. This study aims to investigate the clinicopathological features of diffuse-type gastric cancers with RHOA mutation.MethodsWe performed a thorough review of 87 diffuse-type gastric cancers, including 22 RHOA-mutated and 65 RHOA wild-type gastric cancers.ResultsMost advanced tumors with RHOA mutation appeared as Borrmann type 3 lesions (81 %) developing in the middle (50 %) or distal (32 %) third of the stomach. Histologically, although all of the tumors were predominantly or exclusively composed of poorly cohesive carcinoma, limited tubular differentiation was also observed in 73 % of the RHOA-mutated tumors. Notably, RHOA-mutated tumors more frequently showed a permeative growth pattern at the edge of the mucosal area (59 %) compared with RHOA wild-type tumors (29 %, P = 0.0202). Additionally, the size ratios of the deeply invasive components to the mucosal components were significantly lower in RHOA-mutated tumors [less than 1.45 (median) in 68 % of cases] than in RHOA wild-type tumors (less than 1.45 in 42 % of cases, P = 0.0482). RHOA mutation did not significantly impact survival in this study.ConclusionsThese observations suggest that RHOA mutation may be associated with the growth patterns of diffuse-type gastric cancer but have a limited prognostic impact in isolation. Further studies, including analyses of the other alterations involving the RhoA pathways, such as CLDN18–ARHGAP fusion, as well as functional studies of mutant RhoA, are necessary to clarify the significance of alterations in the RhoA-signaling pathway in diffuse-type gastric cancers.
Highlights
Gastric cancer remains the third leading cause of cancer death worldwide
This study aims to investigate the clinicopathological features of diffuse-type gastric cancers with RHOA mutation
Most advanced tumors with RHOA mutation appeared as Borrmann type 3 lesions (81 %) developing in the middle (50 %) or distal (32 %) third of the stomach
Summary
Gastric cancer remains the third leading cause of cancer death worldwide. Despite improvements in the treatment of gastric cancer, patients with advanced or metastatic disease have a poor prognosis, with 5-year survival rates of approximately 5–15 % for stage IV disease [1, 2]. Several recent studies involving the use of whole-exome or whole-genome sequencing have reported recurrent nonsynonymous mutations of RHOA in a subset of gastric cancers [9,10,11]. The functional assays in our report using small interfering RNA knockdowns and rescue experiments have demonstrated the growth-promoting effects of mutant RhoA [9]. From these observations, mutant RhoA is likely to function in a gainof-function manner and play a key role in the carcinogenesis of diffuse-type gastric cancer. These reports show mutant RhoA is an important cancer driver and is a potential therapeutic target. This study aims to investigate the clinicopathological features of diffuse-type gastric cancers with RHOA mutation
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