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Cellular and Molecular Biology

Lethal clinical outcome and immune desert contexture in refractory gastric cancer harboring CCNE1 amplification and overexpression

British Journal of Cancer (2026)Cite this article

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Abstract

Background

The epithelial-mesenchymal axis frames gastric cancer heterogeneity but mainly captures phenotypic extremes. CCNE1 gain, encompassing amplification or Cyclin E1 overexpression, represents one intermediate state linked to chromosomal instability and therapeutic resistance. However, its clinicopathologic identity and immune features in gastric cancer remain insufficiently characterised.

Methods

We analysed 1273 gastric cancer patients across six independent cohorts: ZSHS (n = 453), TCGA (n = 410), ACRG (n = 300), SMC (n = 43), MSKCC (n = 22), and ZSHS NGS cohort (n = 45). Tumours were classified into CCNE1 gain, epithelial, or mesenchymal subtypes using protein, copy-number, or transcript-level data. Clinicopathologic features, survival outcomes, treatment responses, and immune contexture were evaluated across subtypes.

Results

CCNE1 gain tumours retained E-cadherin positivity but showed increased proliferation, more nerve and venous invasion. They were associated with poor prognosis and reduced response to adjuvant chemotherapy, HER2-targeted therapy, anti-angiogenic agents, and PD-1 blockade independent of epithelial-mesenchymal classification. The immune contexture exhibited an immune-desert phenotype with reduced lymphocyte infiltration, impaired cytotoxicity, increased M2 macrophage polarisation, and elevated TGF-β.

Conclusion

CCNE1 gain delineates a clinic-ready, therapy-refractory subtype of gastric cancer beyond the epithelial-mesenchymal framework, representing over one in ten patients. These tumours preserve epithelial morphology yet exhibit aggressive proliferative and invasive behaviour, coupled with immune desert and myeloid-driven suppression.

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Fig. 1: Lethal prognosis in gastric cancer harbouring CCNE1 amplification and overexpression.
The alternative text for this image may have been generated using AI.
Fig. 2: Multitherapy refractory outcomes in gastric cancer harbouring CCNE1 amplification and overexpression.
The alternative text for this image may have been generated using AI.
Fig. 3: Aggressive proliferative phenotype and local invasion in gastric cancer harbouring CCNE1 amplification and overexpression.
The alternative text for this image may have been generated using AI.
Fig. 4: Immune desert contexture with suppressive remodelling in gastric cancer harbouring CCNE1 amplification and overexpression.
The alternative text for this image may have been generated using AI.

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Data availability

Data and materials generated that are relevant to the results are included in this article. Other data are available from the corresponding author Prof. Xu upon reasonable request.

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Acknowledgements

We would like to thank Dr. Lingli Chen (Department of Pathology, Zhongshan Hospital, Fudan University, Shanghai, China) and Dr. Yunyi Kong (Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China) for their excellent pathological technology help.

Funding

This study was funded by grants from National Natural Science Foundation of China (82203201, 82272786, 82303966, 82373417, 82503945), China Postdoctoral Science Foundation (2023M742327), Shanghai Municipal Natural Science Foundation (23ZR1409900), Shanghai Municipal Health Commission (20254Y0166), Shanghai Pujiang Talents Program (24PJD013), Chenguang Program of Shanghai Education Development Foundation and Shanghai Municipal Education Commission (25CGA05), Natural Science Foundation of Fujian Province (2023J05294) and Clinical Research Fund of Zhongshan Hospital Fudan University (ZSLCYJ202343). All these study sponsors have no roles in the study design, in the collection, analysis and interpretation of data.

Author information

Author notes

  1. These authors contributed equally: Yun Gu, Jieti Wang.

  2. These authors jointly supervised this work: Ruochen Li, Fei Shao, Jiejie Xu.

Authors and Affiliations

  1. Department of Gastrointestinal Surgery, Shanghai Sixth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Yun Gu

  2. National Health Commission Key Laboratory of Glycoconjugate Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China

    Yun Gu, Zhen Ling, Jingquan Liu & Jiejie Xu

  3. Department of Endoscopy, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China

    Jieti Wang

  4. Department of Acute Care Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Chao Lin, Hongyong He & Ruochen Li

  5. Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai, China

    Hao Liu

  6. Department of Oncology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China

    Shao Fei

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Contributions

Y Gu and J Wang for the acquisition of data, interpretation of data, statistical analysis and drafting of the manuscript; Z Ling, J Liu, C Lin, H Liu and H He for technical and material support; R Li, F Shao and J Xu for study concept and design, analysis and interpretation of data, drafting of the manuscript, obtained funding and study supervision.

Corresponding author

Correspondence to Jiejie Xu.

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The authors declare no competing interests.

Ethical approval and consent to participate

The study was approved by the Clinical Research Ethics Committee of Zhongshan Hospital, Fudan University, with the approval number B2025-295. Written informed consent was obtained from each patient included and this study was performed in accordance with the Declaration of Helsinki.

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Gu, Y., Wang, J., Ling, Z. et al. Lethal clinical outcome and immune desert contexture in refractory gastric cancer harboring CCNE1 amplification and overexpression. Br J Cancer (2026). https://doi.org/10.1038/s41416-026-03461-7

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