Immunologic markers and risk of hepatocellular carcinoma in hepatitis B virus‐ and hepatitis C virus‐infected individuals
Jill Koshiol, Ilona Argirion, Zhiwei Liu, Tram Kim Lam, Thomas R. OʼBrien, Kelly J. Yu, Katherine A. McGlynn, Jessica L. Petrick, Lígia A. Pinto, Chien‐jen Chen, Allan Hildesheim, Ruth M. Pfeiffer, Mei‐Hsuan Lee, Hwai‐I Yang
Abstract
Summary 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 ratio quartile 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 OR Q4vQ1 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.