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Mutation spectrum in the Wnt/β-catenin signaling pathway in gastric fundic gland-associated neoplasms/polyps

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Abstract

Frequent activation of the Wnt/β-catenin signaling pathway has recently been demonstrated in gastric adenocarcinoma/neoplasia of chief cell predominant type (GA-CCP/GN-CCP) with submucosal involvement. In this study, we examined the activation status of the Wnt/β-catenin signaling pathway in GN-CCP without submucosal involvement, which is referred to as gastric dysplasia-CCP (GD-CCP). We also examined β-catenin expression and the mutation spectrum of PPP2R1A and Wnt pathway genes in 11 cases of GD-CCP, 25 cases of gastric polyps of fundic gland type (GPs-FG), and 21 cases of GPs-FG with dysplasia (GP-FGD). β-catenin nuclear staining was observed in 3 cases of GD-CCP, none of GPs-FG, and 6 cases of GPs-FGD. Mutations in Wnt pathway genes, including PPP2R1A, were observed in 4 cases of GDs-CCP, 10 cases of GPs-FG, and 7 cases of GPs-FGD. Two of these seven GPs-FGD cases showed β-catenin nuclear staining. However, none of the 4 GD-CCP cases with mutations or the 10 GPs-FG cases with mutations showed β-catenin nuclear staining. PPP2R1A mutations were observed in 1 GD-CCP case and 1 GPs-FGD case. Although the mutation spectra of the Wnt pathway genes in GD-CCP and GP-FG differed, based on the absence of β-catenin nuclear staining despite the genetic alterations, GD-CCP is more similar to GP-FG than to GN-CCP, which shows β-catenin nuclear staining and submucosal involvement. Activation of the Wnt/β-catenin signaling by the β-catenin nuclear transition may be required during progression from GD-CCP to GN-CCP. Furthermore, this is the first report describing PPP2R1A mutations in gastric fundic gland-associated neoplasms.

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Acknowledgments

The authors thank Dr. Minako Hirahashi (Department of Anatomic Pathology, Pathological Sciences, Graduate School of Medical Sciences, Kyushu University), Dr. Yumi Oshiro (Department of Pathology, Matsuyama Red Cross Hospital), Dr. Takehiro Tanaka (Department of Pathology, Okayama University Graduate School of Medicine), Dr. Yutaka Nakashima (Division of Pathology, Japanese Red Cross Fukuoka Hospital), Dr. Tetsumi Yamane (Department of Pathology, Tottori Red Cross Hospital), Dr. Fumiyoshi Fushimi (Department of Pathology, National Kyushu Cancer Center), Dr. Shinji Kono (Division of Clinical Pathology, Harasanshin Hospital), Dr. Shuichi Ohara (Department of Gastroenterology, Tohoku Rosai Hospital), Dr. Koyu Suzuki (Department of Pathology, St Luke’s International Hospital), and Dr. Takeshi Yano (Department of Surgery, Asoka Hospital) for kindly providing samples and clinical information, Dr. Ayumi Osako (Department of Gastroenterology, Tottori Seikyo Hospital). We also wish to thank Mrs. Keiko Mitani (Department of Human Pathology, Juntendo University School of Medicine) for her expert technical assistance. We also thank the Laboratory of Molecular and Biochemical Research, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan, for technical assistance.

Funding

This work was supported, in part, by a Grant-in-Aid for General Scientific Research from the Ministry of Education, Science, Sports, and Culture (#26670286 to Tsuyoshi Saito, #24590429 to Hiroyuki Mitomi and #26460428 to Takashi Yao), Tokyo, Japan.

Conflict of interest

The authors declare that there are no conflicts of interest to disclose.

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Authors and Affiliations

  1. Department of Human Pathology, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo, 113-8421, Japan

    Se-Yong Lee, Tsuyoshi Saito, Yasuhiro Hidaka, Takashi Murakami, Ryosuke Nomura & Takashi Yao

  2. Department of Gastroenterology, Juntendo University School of Medicine, Tokyo, Japan

    Se-Yong Lee, Yasuhiro Hidaka, Takashi Murakami, Ryosuke Nomura & Sumio Watanabe

  3. Department of Surgical and Molecular Pathology, Dokkyo University School of Medicine, Kitakobayashi 880, Mibumachi, Shimotsugagun, Tochigi, 321-0293, Japan

    Hiroyuki Mitomi

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  1. Se-Yong Lee
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Correspondence to Tsuyoshi Saito.

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Lee, SY., Saito, T., Mitomi, H. et al. Mutation spectrum in the Wnt/β-catenin signaling pathway in gastric fundic gland-associated neoplasms/polyps. Virchows Arch 467, 27–38 (2015). https://doi.org/10.1007/s00428-015-1753-4

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