Biomarkers for Early Detection of Hepatitis B-Related Hepatocellular Carcinoma in Hispanics

Infection with hepatitis B virus (HBV), is the most common risk factor for the development of hepatocellular carcinoma (HCC) worldwide. HBV infection can cause HCC before liver cirrhosis, thereby affecting younger persons. A recent study from our South American Liver Research Network (SALRN) found that HBV-related HCC occurs at earlier ages in Hispanics than HCC related to other liver diseases. This HBV complication is of particular concern as HCC occurs outside of the “standard” recommended age for starting HCC screening. Currently, individuals with HBV are advised to undergo ultrasonography of the liver every 6 months with the goal of “visually” identifying a tumor small enough that might be amenable to curative treatment. This visual screening approach has poor adherence due to a variety of issues, such as time commitment, and is dependent on the ultrasound operator expertise. We hypothesize that a non-visual screening approach with standardized immune-related blood biomarkers may be a sensible alternative approach. Our group recently identified a series of immune markers detected in serum of patients with hepatitis that were able to predict the future development of HCC, even when the cancer occurred two years later. In this project, we will investigate whether the hyper-immune environment, product of the continuous presence of the virus in the liver, could lead to further alterations in measurable immune analytes in serum so to predict early HCC development. Using our multinational on-going networks of SALRN and ESCALON in Latin America, we propose to cross-sectionally and prospectively evaluate peripheral immune variations in Hispanic HBV-infected individuals as markers to predict early HCC development. In Specific Aim 1, we will determine if novel immune signatures in the serum of persons with chronic HBV infection and hepatocellular carcinoma show differential expression compared to controls. We will evaluate a pre-defined panel of immune analytes via multiplex cytokine analysis comparing HBV infected HCC cases with controls In Specific Aim 2, we will validate a novel immune signature in serum for identifying those who will progress to hepatocellular carcinoma in persons with chronic HBV infection. We will prospectively collect samples from HBV-infected Hispanics in two regions of high HBV prevalence in South America and validate our HCC-immune signature In Specific Aim 3, we will evaluate intrahepatic immune markers in HBV-infected livers at risk for HCC. We will use spatial genomics intersected with HBV staining in liver biopsies from Latin America to further understand the mechanisms behind immunomodulation of HBV-related HCC This study will provide innovative data that will impact Hispanic persons living with chronic HBV infection, seeking to create a new standard of care for liver cancer screening in this population.