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Exploration of molecular markers related to chemotherapy efficacy of hepatoid adenocarcinoma of the stomach

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Abstract

Purpose

Preoperative neoadjuvant chemotherapy may not improve the prognosis of patients with hepatoid adenocarcinoma of the stomach (HAS), a rare pathological type of gastric cancer. Thus, the study aimed at the genomic and transcriptomic impacts of preoperative chemotherapy on HAS.

Methods

Patients with HAS who underwent surgical resection at Peking University Cancer Hospital were retrospectively included in this study. Whole exome sequencing and transcriptome sequencing were performed on pre-chemotherapy, non-chemotherapy and post-chemotherapy samples. We then compared the alterations in molecular markers between the post-chemotherapy and non-chemotherapy groups, and between the chemotherapy-effective and chemotherapy-ineffective groups, respectively.

Results

A total of 79 tumor samples from 72 patients were collected. Compared to the non-chemotherapy group, the mutation frequencies of several genes were changed after chemotherapy, including TP53. In addition, there was a significant increase in the frequency of frameshift mutations and cytosine transversion to adenine (C > A), appearance of COSMIC signature 6 and 14, and a reduced gene copy number amplification. Interestingly, the same phenomenon was observed in chemotherapy-ineffective patients. In addition, many HAS patients had ERBB2, FGFR2, MET and HGF gene amplification. Moreover, the expression of immune-related genes, especially those related to lymphocyte activation, was down-regulated after chemotherapy.

Conclusion

Chemotherapy is closely associated with changes in the molecular characteristics of HAS. After chemotherapy, at genomic and transcriptome level, many features were altered. These changes may be molecular markers of poor chemotherapeutic efficacy and play an important role in chemoresistance in HAS. In addition, ERBB2, FGFR2, MET and HGF gene amplification may be potential therapeutic targets for HAS.

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Data availability

The raw sequence data reported in this paper have been deposited in the Genome Sequence Archive (Genomics, Proteomics & Bioinformatics 2021) in National Genomics Data Center (Nucleic Acids Res 2022), China National Center for Bioinformation / Bei**g Institute of Genomics, Chinese Academy of Sciences (GSA-Human: HRA005627) that are publicly accessible at https://ngdc.cncb.ac.cn/gsa-human.

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Acknowledgements

We would like to thank all the patients who participated in this study and the staff who provided medical care. We also thank those who performed the sequencing and analysis (Berry Genomics Corporation). This work was supported by Capital’s Funds For Health Improvement and Research (CFH 2022-4-1025), Bei**g Youth Talent Plan (QML20191101) and Science Foundation of Peking University Cancer Hospital (PY202316).

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Author notes

  1. **gtao Wei, Ke Ji and Yue Zhang contributed equally to this work.

Authors and Affiliations

  1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Bei**g), Department of Gastrointestinal Cancer Center, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Bei**g, 100142, China

    **gtao Wei, Ke Ji, Ji Zhang, **aojiang Wu, **n Ji, Kai Zhou, Xuesong Yang, Anqiang Wang & Zhaode Bu

  2. Bei**g Key Laboratory of Preclinical Research and Evaluation for Cardiovascular Implant Materials, Animal Experimental Centre, Fuwai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Bei**g, 100037, China

    Yue Zhang

  3. The Cardiomyopathy Research Group at Fuwai Hospital, State Key Laboratory of Cardiovascular Disease, National Center for Cardiovascular Diseases, Bei**g, 100037, China

    Yue Zhang

  4. Berry Genomics Corporation, Bei**g, 102206, China

    Hongfeng Lu

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  1. **gtao Wei
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Contributions

These authors contributed equally: J.W.,K.J. and Y.Z. All authors read and approved the final manuscript. Conceptualization: A.W., J.W., Z.B. and J.J. Investigation: J.W., A.W., K.J., Y.Z., J.Z., X.W., X.J., K.Z., X.Y., H.L. Bioinformatic and statistical analyses: Y.Z., H.L., A.W. and J.W. Writing—original draft: J.W. Writing—review & editing: A.W. and K.J. Project administration: A.W. Supervision: Z.B. and J.J. Funding acquisition: A.W. and J.W.

Corresponding authors

Correspondence to Anqiang Wang or Zhaode Bu.

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The study of human tumor samples was performed according to the Declaration of Helsinki and Good Clinical Practice and approved by the Ethnical Committee of Peking Cancer Hospital.

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Wei, J., Ji, K., Zhang, Y. et al. Exploration of molecular markers related to chemotherapy efficacy of hepatoid adenocarcinoma of the stomach. Cell Oncol. 47, 677–693 (2024). https://doi.org/10.1007/s13402-023-00892-9

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