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Soluble CD137 and risk of hepatocellular carcinoma: nested case–control studies in cohorts in Shanghai and Singapore



The majority of hepatocellular carcinoma (HCC) cases occur in the presence of cirrhosis. Biomarkers of cirrhosis-associated immune dysfunction such as CD8+ T cell cytokines could aid HCC risk assessment.


CD8+ T cell cytokines were determined in pre-diagnostic serum in two studies including 315 HCC case–control pairs in the Shanghai Cohort Study (SCS) and 197 pairs in the Singapore Chinese Health Study (SCHS). Conditional logistic regression was used to estimate odds ratio (OR) and 95% confidence interval (CI) for HCC with levels of five cytokines—soluble CD137 (sCD137), soluble Fas (sFas), perforin, macrophage inflammatory protein 1-beta (MIP-1β), and tumour necrosis factor alpha (TNF-α).


sCD137 levels were significantly higher in HCC cases than controls in both cohorts (Ps < 0.001). Compared with the lowest quartile, multivariable-adjusted ORs (95% CI) of HCC for the highest sCD137 quartile were 3.79 (1.73, 8.30) in the SCS and 3.49 (1.44, 8.48) in the SCHS. The sCD137-HCC association was independent of hepatitis B seropositivity and follow-up time. No other cytokine was consistently associated with HCC risk.


sCD137 was associated with higher risk of HCC in two studies nested in general population cohorts. sCD137 may be a long-term risk marker of HCC development.

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Fig. 1: Distributions of serum cytokines within hepatocellular carcinoma cases and matched controls in The Shanghai Cohort Study (SCS) and The Singapore Chinese Health Study (SCHS).

Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

Code availability

The computer code that support the findings of this study is available from the corresponding author upon reasonable request.


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We thank the Singapore Cancer Registry for the identification of incident cancer cases among participants of the Singapore Chinese Health Study and Siew-Hong Low of the National University of Singapore for supervising the fieldwork of the Singapore Chinese Health Study. We also thank Ms. Xue-Li Wang of the Shanghai Cancer Institute for supervising the field work of the Shanghai Cohort Study and the Shanghai Cancer Registry for assistance with identification of cancer outcomes in the Shanghai Cohort Study. This project used the UPMC Hillman Cancer Center Cancer Biomarkers Facility: Luminex Core Laboratory.


The Shanghai Cohort Study was supported by the National Institutes of Health (NIH) of the United States (grants # R01CA043092, R01CA144034, and UM1CA182876), and the Singapore Chinese Health Study was supported by NIH (grants # R01CA080205, R01CA144034, and UM1CA182876). The current work was also partially supported by the NIH grants # R01CA255809 and P30CA047904. CET is supported through a NIH training grant (grant # T32 CA186873). The content is solely the responsibility of the authors and does not necessarily represent the official views of NIH.

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Authors and Affiliations



The work reported in the paper has been performed by the authors, unless clearly specified in the text. CET: conceptualisation, formal analysis, visualisation, writing of the original draft of the manuscript, writing—reviewing and editing. JJA, ALK, BD: conceptualisation, methodology, writing—reviewing and editing. HNL: conceptualisation, writing—reviewing and editing. AJ: formal analysis. W-PK, Y-TG: data curation, resources, writing—reviewing and editing. JA-H: data curation, project administration. RW: formal analysis. AL: data curation, writing—reviewing and editing. JB: investigation, writing—reviewing and editing. J-MY: conceptualisation, data curation, resources, formal analysis, funding acquisition, supervision, writing—reviewing and editing.

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Correspondence to Jian-Min Yuan.

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The authors declare no competing interests.

Ethics approval and consent to participate

The Shanghai Cohort Study has been approved by the Institutional Review Boards of the Shanghai Cancer Institute and the University of Pittsburgh. The Singapore Chinese Health Study has been approved by the Institutional Review Boards of the National University of Singapore and the University of Pittsburgh. Informed consent was obtained from all participants. The present study has been approved by the University of Pittsburgh Human Research Protection Office and was conducted in accordance with the Declaration of Helsinki.

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Thomas, C.E., Adibi, J.J., Kuipers, A.L. et al. Soluble CD137 and risk of hepatocellular carcinoma: nested case–control studies in cohorts in Shanghai and Singapore. Br J Cancer 128, 2081–2088 (2023).

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