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Cellular and Molecular Biology

A novel high-risk subpopulation identified by CTSL and ZBTB7B in gastric cancer

British Journal of Cancer volume 127, pages 1450–1460 (2022)Cite this article

Subjects

Abstract

Background

Gastric cancer (GC) is characterised by a heterogeneous tumour microenvironment (TME) that is closely associated with the response to treatment, especially immunotherapies. However, most previous GC molecular subtyping systems need complex gene signatures and examination methods, restricting their clinical applications. Thus, we developed a new TME-based molecular subtype using only two genes.

Methods

Nine independent GC cohorts at the tissue- or single-cell level with more than 2000 patients were used in this study, including data we examined by single-cell sequencing, quantitative RT-PCR and immunochemistry/immunofluorescence staining. Nine different methods, five existing molecular subtypes and a series of signatures were used to evaluate the TME and molecular characteristics of GC.

Results

We established a CTSL/ZBTB7B subtyping system and uncovered the novel CTSLHighZBTB7BLow high-risk subgroup, but characterised by relative higher immune cell infiltration and lower tumour purity. This subgroup demonstrate higher levels of immune checkpoints and more enrichment of cancer-related pathways compared with other cases.

Conclusions

We identified a high-risk subpopulation with unique TME features based on expressions of CTSL and ZBTB7B, suggesting a counterbalancing phenotype between immunostimulatory and immunosuppressive mechanisms. This subtyping system could be used to select treatment and management strategies for GC.

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Fig. 1: Stratification based on the expression levels of CTSL and ZBTB7B was associated with GC prognosis.
Fig. 2: Prognostic value of CTSL/ZBTB7B stratification according to TNM stage.
Fig. 3: The CTSLHighZBTB7BLow risk subpopulation feature by high immune infiltrates and low tumour purity.
Fig. 4: Exploration of potential reasons accounting for the poor survival in CTSLHighZBTB7BLow patients.
Fig. 5: The CTSL/ZBTB7B stratification system shows prognostic significance in Pan-cancer.
Fig. 6

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Data availability

Available of public GC datasets are described in the ‘Methods’ section. The data that support this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We acknowledge the TCGA and GEO project. We thank developers of each dataset, method and package used in this study. We would like to thank the Affiliated Hospital of Jiangnan University for providing GC samples. We thank Yong Zhang (South China University of Technology) for their helpful comments.

Funding

This work was supported by grants from the National Natural Science Foundation of China (82002550, 81972220 and 82173063), Medical Key Professionals Program of Jiangsu Province (AF052141), Wuxi Taihu Lake Talent Plan for Leading Talents in Medical and Health Profession, Wuxi Medical Key Discipline (ZDXK2021002) and Wuxi Medical Innovation Team (CXTP003).

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Authors and Affiliations

  1. Wuxi Cancer Institute, Affiliated Hospital of Jiangnan University, 214062, Wuxi, Jiangsu, China

    Kaisa Cui, Surui Yao, Bingxin Liu, Shengbai Sun & Zhaohui Huang

  2. Laboratory of Cancer Epigenetics, Wuxi School of Medicine, Jiangnan University, 214122, Wuxi, Jiangsu, China

    Kaisa Cui, Bingxin Liu, Shengbai Sun, Liang Gong & Zhaohui Huang

  3. Key Laboratory of Carbohydrate Chemistry & Biotechnology, Ministry of Education, School of Biotechnology, Jiangnan University, 214122, Wuxi, Jiangsu, China

    Liang Gong

  4. Computer Vision Lab, Department of Electrical Engineering, California Institute of Technology, Pasadena, CA, 91125, USA

    Qilin Li

  5. Department of Surgical Oncology, Affiliated Hospital of Jiangnan University, 214122, Wuxi, Jiangsu, China

    Bojian Fei

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  1. Kaisa Cui
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Contributions

KC, ZH and BF designed the study. KC, BL and QL performed bioinformatics analyses, proofread and visualisation. SY, BL, SS and BF performed GC samples collective and information maintenance. KC and ZH designed the wet-lab experiments. SY, BL and LG performed the wet-lab experiments. KC, SY and BL analysed and visualised the wet-lab experiment results. KC and BL performed graphic abstract. All authors discussed the results. KC, ZH and BF wrote the manuscript.

Corresponding authors

Correspondence to Bojian Fei or Zhaohui Huang.

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This study was approved by the Clinical Research Ethics Committees of Affiliated Hospital of Jiangnan University and written informed consent was obtained from all the participants.

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Cui, K., Yao, S., Liu, B. et al. A novel high-risk subpopulation identified by CTSL and ZBTB7B in gastric cancer. Br J Cancer 127, 1450–1460 (2022). https://doi.org/10.1038/s41416-022-01936-x

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