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Early gastric cancer with RhoGAP fusion is linked to frequent nodal metastasis and a part of microtubular–mucocellular histology

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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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Authors and Affiliations

  1. Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

    Hiroto Noda, Seiji Sakata, Satoko Baba, Yuki Togashi, Kaoru Nakano, Chiina Hata, Manabu Takamatsu, Emiko Sugawara, Noriko Yamamoto, Kengo Takeuchi & Hiroshi Kawachi

  2. Department of Gastroenterology, Nippon Medical School Hospital, Tokyo, Japan

    Hiroto Noda & Katsuhiko Iwakiri

  3. Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan

    Seiji Sakata, Satoko Baba, Yuki Togashi & Kengo Takeuchi

  4. Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

    Seiji Sakata, Satoko Baba, Yuki Togashi, Kaoru Nakano, Manabu Takamatsu, Emiko Sugawara, Noriko Yamamoto, Kengo Takeuchi & Hiroshi Kawachi

  5. Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

    Toshiaki Hirasawa, Izuma Nakayama & Junko Fujisaki

  6. Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan

    Izuma Nakayama

  7. Department of Human Pathology, Tokyo Medical and Dental University, Tokyo, Japan

    Chiina Hata

  8. Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan

    Souya Nunobe

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  1. Hiroto Noda
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Contributions

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.

Corresponding author

Correspondence to Hiroshi Kawachi.

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Conflict of Interest

The authors declare no conflict of interest for this article.

Ethical approval

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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