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. 2016 Apr;19(2):403-411.
doi: 10.1007/s10120-015-0493-0. Epub 2015 Apr 1.

RHOA mutation in diffuse-type gastric cancer: a comparative clinicopathology analysis of 87 cases

Tetsuo Ushiku  1 , Shumpei Ishikawa  2 , Miwako Kakiuchi  3   4 , Atsushi Tanaka  1 , Hiroto Katoh  5 , Hiroyuki Aburatani  3 , Gregory Y Lauwers  6 , Masashi Fukayama  1
Affiliations

RHOA mutation in diffuse-type gastric cancer: a comparative clinicopathology analysis of 87 cases

Tetsuo Ushiku et al. Gastric Cancer. 2016 Apr.

Abstract

Background: Recent 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.

Methods: We performed a thorough review of 87 diffuse-type gastric cancers, including 22 RHOA-mutated and 65 RHOA wild-type gastric cancers.

Results: 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. 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.

Conclusions: These 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.

Keywords: Diffuse type; Gastric cancer; Mutation; RHOA.

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Figures

Fig. 1
Fig. 1
Histology of RHOA-mutated gastric cancers. Poorly cohesive carcinoma is the predominant component (a), including signet-ring cells in many cases (b). Focal tubular differentiation is frequently recognized (c), and a mucinous component may also be present (d)
Fig. 2
Fig. 2
Growth patterns at the edge of the intramucosal component. The expansile pattern demonstrates destructive invasion with a relatively well-defined margin (indicated by the dotted line) at the advancing edge (a). In the permeative pattern, neoplastic cells infiltrate between the normal pits or glands in the middle layer of the lamina propria, with no recognizable margin to the growth (b). Neoplastic cells are indicated by arrows
Fig. 3
Fig. 3
Correlation between the sizes of the intramucosal components and those of the submucosal or deeper areas of each case. Arrows at the lower right indicate cases of linitis plastica type cancer (n = 5)
Fig. 4
Fig. 4
Kaplan–Meier survival plot according to RHOA mutation status among patients with the stage II–IV disease. RHOA mutation was not significantly associated with disease-specific survival (a) or disease-free survival (b) of patients with diffuse-type gastric cancer
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