Associations between circulating immunologic markers and HCC in individuals with chronic HCV infection.

Abstract

e16271 Background: Although immunologic proteins have been associated with hepatocellular carcinoma (HCC) development, little is known about whether these associations are with HCC or underlying fibrosis/cirrhosis. Methods: We sampled 92 HCC cases and 184 controls from The Hepatitis C Antiviral Long-Term Treatment against Cirrhosis (HALT-C) prospective study. All participants were chronically infected with hepatitis C virus (HCV) and presented with advanced fibrosis or cirrhosis. Conditional logistic regression was used to compare baseline plasma levels for 248 markers in individuals who developed HCC vs. controls. We also evaluated the association between immune markers and cirrhosis (Ishak 5-6) vs. fibrosis (Ishak 3-4) among controls. We assessed biological pathways associated with HCC development compared to controls. P-values for individual markers and pathways were corrected for multiple testing; p-value < 0.05 was used to determine significance among a-priori markers. Results: After multivariable adjustment, three a-priori markers: ICAM-1 (Q 4v1 OR: 8.1; 95%CI: 2.8-23.4), HGF (Q 4v1 OR: 3.1; 95%CI: 1.2-8.0), SCF (Q 4v1 OR: 0.4; 95%CI: 0.2-0.9) and seven novel markers: ACE2 (Q 4v1 OR: 5.2; 95%CI: 1.8-15.2), CDH1 (Q 4v1 OR: 3.2; 95%CI: 1.3-7.5), CD244 (Q 4v1 OR: 4.6; 95%CI: 1.8-12.0), OPG (Q 4v1 OR: 6.1; 95%CI: 2.1-17.4), TNFRSF10A (Q 4v1 OR: 3.3; 95%CI: 1.4-8.1), NOTCH1 (Q 4v1 OR: 2.8; 95%CI: 1.2-6.5), and HAOX1 (Q 4v1 OR: 3.4; 95%CI: 1.3-8.7) were significantly associated with HCC development. All three a-priori markers, as well as ACE2, CDH1, and CD244, were shown to be significantly associated with cirrhosis vs. fibrosis. Biological pathways related to apoptotic process, cellular response to cytokine stimulus, extracellular matrix organization and inflammatory response were associated with HCC development. Conclusions: We confirmed the association of ICAM-1, HGF, and SCF and identified 7 additional proteins associated with HCV-related HCC in the context of underlying fibrosis/cirrhosis.