Abstract
Introduction
Gastric cancer with fusion genes involving the Rho GTPase-activating protein domain (RhoGAP-GC) is mainly included in the genomically stable type of The Cancer Genome Atlas classification. Clinical implications and histological characteristics of RhoGAP-GC in the early phase remain unclear.
Methods
We analyzed 878 consecutive pT1b GCs for RhoGAP and its partner genes using fluorescence in situ hybridization assay.
Results
RhoGAP fusion was detected in 57 (6.5%) GCs. Univariate analysis revealed that female sex, middle–lower third tumor location, advanced macroscopic type, tumor diameter > 2 cm, pT1b2, lymphatic invasion, venous invasion, negative EBER-ISH, and RhoGAP fusion were significantly associated with lymph node metastasis (LNM). Multivariate analysis presented RhoGAP fusion, lymphatic invasion, tumor diameter > 2 cm, advanced macroscopic type, venous invasion, and middle–lower third tumor location as independent risk factors for LNM. Notably, RhoGAP fusion had the highest odds ratio (3.92) for LNM among analyzed parameters (95% CI 2.12–7.27; p < 0.001). Compared to non-RhoGAP-GCs, RhoGAP-GCs were significantly frequent in younger females and showed the highest incidence of lymphatic invasion (56.2%) and LNM (49.1%) (p < 0.001). Histologically, microtubular architecture with pseudo-trabecular interconnection and small aggregations of tumor cells with a varied amount of cytoplasmic mucin, named “microtubular–mucocellular (MTMC) histology,” was found in 93.0% (53 of 57) of RhoGAP-GCs in the intramucosal area. MTMC histology showed high sensitivity and negative predictive value (93.0% and 99.4%, respectively) for RhoGAP fusion, albeit positive predictive value is low (34.9%).
Conclusion
RhoGAP-GC is linked to a characteristic MTMC histology and a high incidence of LNM.
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Data availability
The datasets generated and/or analyzed during the present study are not publicly available in accordance with the policy of JFCR but may be available from the corresponding author by submitting a research proposal, which will be reviewed for scientific merit and feasibility.
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Acknowledgements
We thank Ms. Miyuki Kogure, Ms. Tomoyo Kakita, Ms. Keiko Shiozawa, Ms. Mayumi Ogawa, Mr. Motoyoshi Iwakoshi, and Mr. Shuhei Ishii for their technical support.
Funding
This research was supported by the JSPS KAKENHI Grant Numbers JP16K08661 and JP21K06918.
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HN, SS, KT, and HK developed the study concept and design, interpretation of data, and statistical analysis and SS, SB, KT, and HK developed the methodology; HN, KN, CH, MT, ES, NY, and HK provided the histopathological diagnoses; HN, SS, KT, and HK wrote, reviewed, and revised the paper; TH, JF, and SN provided data acquisition. SB, YT, IN, and KI provided technical and material support. All the authors have read and approved the final manuscript.
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This study was approved by the institutional review board of the Japanese Foundation for Cancer Research (2022-GB-104). This study was conducted in accordance with the principles of the Declaration of Helsinki.
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Noda, H., Sakata, S., Baba, S. et al. Early gastric cancer with RhoGAP fusion is linked to frequent nodal metastasis and a part of microtubular–mucocellular histology. Gastric Cancer (2024). https://doi.org/10.1007/s10120-024-01507-4
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DOI: https://doi.org/10.1007/s10120-024-01507-4