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. 2021 Sep;54(6):833-842.
doi: 10.1111/apt.16524. Epub 2021 Jul 19.

Immunologic markers and risk of hepatocellular carcinoma in hepatitis B virus- and hepatitis C virus-infected individuals

Jill Koshiol  1 , Ilona Argirion  1 , Zhiwei Liu  1 , Tram Kim Lam  2 , Thomas R O'Brien  1 , Kelly Yu  1 , Katherine A McGlynn  1 , Jessica L Petrick  1   3 , Ligia Pinto  4 , Chien-Jen Chen  5   6 , Allan Hildesheim  1 , Ruth M Pfeiffer  1 , Mei-Hsuan Lee  7 , Hwai-I Yang  5
Affiliations

Immunologic markers and risk of hepatocellular carcinoma in hepatitis B virus- and hepatitis C virus-infected individuals

Jill Koshiol et al. Aliment Pharmacol Ther. 2021 Sep.

Abstract

Background: Clinical and experimental studies suggest immunologic proteins contribute to hepatocellular carcinoma (HCC) development.

Aim: To evaluate circulating immunologic markers and HCC risk.

Methods: From a Taiwanese cohort of chronically hepatitis B virus (HBV)-infected individuals followed over time (REVEAL-HBV), we sampled 175 who developed HCC, 117 cirrhosis only, and 165 non-cirrhotic controls. From a similar Taiwanese cohort of chronically hepatitis C virus (HCV)-infected individuals (REVEAL-HCV), we included 94 individuals who developed HCC, 68 cirrhosis only and 100 non-cirrhotic controls. We compared pre-diagnostic plasma levels of 102 markers in HCC cases to non-cirrhotic and cirrhotic controls using polytomous logistic regression. A priori markers included insulin-like growth factor binding protein-3 (IGFBP-3), intercellular adhesion molecule 1 (ICAM-1) and interleukin 6 (IL-6). P-values for other markers were corrected for multiple testing (false discovery rate = 10%).

Results: In both REVEAL-HBV and REVEAL-HCV, increasing levels of ICAM-1 were associated with increased risk of HCC compared to non-cirrhotic controls (P-trend 0.02 and 0.001, respectively). In both REVEAL-HBV and REVEAL-HCV, two novel markers [C-X-C motif chemokine 11 (CXCL11) and hepatocyte growth factor (HGF)] were positively associated [strongest odds ratioquartile 4 versus 1 (OR) 4.55 for HGF in HCV], while two [complement factor H related 5 (CFHR5) and stem cell factor (SCF)] were negatively associated (strongest ORQ4vQ1 0.14 for SCF in HCV) with development of HCC compared to non-cirrhotic controls.

Conclusions: We confirmed the association for ICAM-1 and identified 4 additional proteins associated with HBV- and HCV-related HCC. These findings highlight the importance of immunologic processes in HBV- and HCV-related HCC.

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Conflict of interest statement

Potential competing interests: No authors have any relevant conflicts of interest.

Figures

Figure 1
Figure 1
Flowchart of study participants in REVEAL-HBV and REVEAL-HCV included in this analysis.
Figure 2
Figure 2
Flowchart of immunologic measurements and categorization in REVEAL-HBV and REVEAL-HCV.
Figure 3
Figure 3
P-trend values and odds ratios from tests of association between HCC versus non-cirrhotic controls and all markers modeled as ordinal categorical variables* in A) REVEAL-HBV, where in addition to the a priori markers IGFBP-3 (p-trend 1.4×10–7), ICAM-1 (p-trend 0.02), and IL-6 (p-trend 0.05), 19 markers were associated with HCC using p<0.05, and B) REVEAL-HCV, where in addition ICAM-1 (p-trend 0.001), 17 markers were associated with HCC using p<0.05.
Figure 4
Figure 4
All a priori makers and novel circulating immunologic markers associated with HCC versus non-cirrhotic controls in both REVEAL-HBV and REVEAL-HCV.
See this image and copyright information in PMC

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References

    1. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer. 2006;118(12):3030–3044. - PubMed
    1. Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ. Estimations of worldwide prevalence of chronic hepatitis B virus infection: a systematic review of data published between 1965 and 2013. Lancet. 2015;386(10003):1546–1555. - PubMed
    1. Polaris Observatory HCVC. Global prevalence and genotype distribution of hepatitis C virus infection in 2015: a modelling study. Lancet Gastroenterol Hepatol. 2017;2(3):161–176. - PubMed
    1. Park SH, Rehermann B. Immune responses to HCV and other hepatitis viruses. Immunity. 2014;40(1):13–24. - PMC - PubMed
    1. Li JF, Dai XP, Zhang W, et al. Upregulation of microRNA-146a by hepatitis B virus X protein contributes to hepatitis development by downregulating complement factor H. MBio. 2015;6(2). - PMC - PubMed

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