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

Hiroto Noda; Seiji Sakata; Satoko Baba; Yuki Togashi; Kaoru Nakano; Toshiaki Hirasawa; Izuma Nakayama; Chiina Hata; Manabu Takamatsu; Emiko Sugawara; Noriko Yamamoto; Junko Fujisaki; Souya Nunobe; Katsuhiko Iwakiri; Kengo Takeuchi; Hiroshi Kawachi

doi:10.1007/s10120-024-01507-4

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

Gastric Cancer. 2024 May 16. doi: 10.1007/s10120-024-01507-4. Online ahead of print.

Authors

Hiroto Noda^{1

2}, Seiji Sakata^{1

3

4}, Satoko Baba^{1

3

4}, Yuki Togashi^{1

3

4}, Kaoru Nakano^{1

4}, Toshiaki Hirasawa⁵, Izuma Nakayama^{5

6}, Chiina Hata^{1

7}, Manabu Takamatsu^{1

4}, Emiko Sugawara^{1

4}, Noriko Yamamoto^{1

4}, Junko Fujisaki⁵, Souya Nunobe⁸, Katsuhiko Iwakiri², Kengo Takeuchi^{1

3

4}, Hiroshi Kawachi^{9

10}

Affiliations

¹ Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
² Department of Gastroenterology, Nippon Medical School Hospital, Tokyo, Japan.
³ Pathology Project for Molecular Targets, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁴ Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁵ Department of Gastroenterology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁶ Department of Gastroenterology and Gastrointestinal Oncology, National Cancer Center Hospital East, Kashiwa, Japan.
⁷ Department of Human Pathology, Tokyo Medical and Dental University, Tokyo, Japan.
⁸ Department of Gastroenterological Surgery, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan.
⁹ Division of Pathology, Cancer Institute, Japanese Foundation for Cancer Research, Tokyo, Japan. hiroshi.kawachi@jfcr.or.jp.
¹⁰ Department of Pathology, Cancer Institute Hospital, Japanese Foundation for Cancer Research, Tokyo, Japan. hiroshi.kawachi@jfcr.or.jp.

PMID: 38755445
DOI: 10.1007/s10120-024-01507-4

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.

Keywords: Early gastric cancer; Fusion gene; Lymph node metastasis; Microtubular–mucocellular pattern; RhoGAP.