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An exploration of gastric cancer with heterogeneous mismatch repair status

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Abstract

Survival benefits or symptom alleviation from immune checkpoint blockade therapy can be seen in microsatellite instability-high (MSI-H) cases. However, genetic heterogeneity within a specific subgroup of MSI-H tumors may be associated with poor response and prognosis. We investigated the molecular changes and microsatellite status of the cases with heterogeneous MMR protein staining by polymerase chain reaction (PCR) and next-generation sequencing (NGS). Data from 3723 patients with gastric cancer were retrospectively analyzed to determine the mismatch repair (MMR) status by performing immunohistochemical staining of four major MMR proteins (MLH1, PMS2, MSH2, and MSH6). When heterogeneous MMR protein staining result was positive, PCR and NGS were performed. Heterogeneous MMR protein staining was observed in 12 cases. In microsatellite stable (MSS) cases, TP53 mutation appeared to accompany heterogeneous staining (HS) of MLH1. However, TP53 variation was not observed with MSI-H occurrence. Cases showing heterogeneous MSH6 protein staining revealed MSH6 mutations. Some cases with the same MMR protein staining set had varying MSI results. In one case whose primary and metastatic foci presented MLH1-HS and PMS2-HS, the microsatellite status was classified as MSS and MSI-H, respectively. Moreover, HS was also found in multiple biopsies and surgical specimens. This study found a preliminary relationship between heterogeneously stained MSH6 or MLH1 proteins and their gene mutations, as well as between MSI-H/TP53 − and MSS/TP53 + tumors. The microsatellite status of patients with heterogeneous MMR protein staining is unpredictable. Given the heterogeneity of mismatch repair, microsatellite status should be assessed for all specimens if sufficient specimens can be obtained.

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Funding

This work was supported by Beijing Natural Science Foundation (Z200015 to XT.Z) and 2020 JingJian•TongShu Microsatellite Instability Research Foundation project (JJTS2020-004).

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Author notes

  1. Xinyu Wang and Kang Jiang contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Pathology, Peking University Cancer Hospital and Institute, Haidian District, 52 Fucheng Road, 100142, Beijing, China

    Xinyu Wang, Kang Jiang, Yajie Hu, Xinya Zhao, Lisha Yin, Xinting Diao, Xiuli Ma & Yu Sun

  2. Department of Pathology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China

    Xinyu Wang

  3. Medical Affairs, 3D Medicines Inc., Shanghai, China

    Yu Xu & Yuezong Bai

  4. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Gastrointestinal Cancer Center, Peking University Cancer Hospital and Institute, Haidian District, 52 Fucheng Road, 100142, Beijing, China

    Yan Zhang & Ziyu Li

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Contributions

All authors contributed to the research process. Manuscript preparation was performed by Xinyu Wang, Kang Jiang, Yajie Hu, Xinya Zhao, Lisha Yin, Xinting Diao, Xiuli Ma, Zan Yhang, Yu Xu, Yuezong Bai, Yu Sun, and Ziyu Li. Procedures and data analysis were performed by Xinyu Wang, and Kang Jiang. Drafting, conception, and design of the research was done by Yu Sun and Ziyu Li. All authors read and approved the final manuscript.

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Correspondence to Ziyu Li or Yu Sun.

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Human samples and clinical data were collected and used in accordance with the principles of the Declaration of Helsinki and approved by the Ethics committee of Peking University Cancer Hospital. All participants provided written informed consents.

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Wang, X., Jiang, K., Hu, Y. et al. An exploration of gastric cancer with heterogeneous mismatch repair status. Virchows Arch 482, 517–523 (2023). https://doi.org/10.1007/s00428-023-03506-9

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