Hepatitis B-Associated Hepatocellular Carcinoma: Variation in Therapeutic Response Mediated by Viral Integration

Lay summary

Hepatocellular carcinoma (HCC), a type of primary liver cancer, is one of the most common causes of cancer death globally. The most common predisposing condition for HCC is infection with the hepatitis B virus (HBV), which is common in Africa and Asia. Studies have shown that liver cancer associated with HBV (HBV-HCC) in Asia and Africa is more aggressive than is liver cancer associated with other conditions and in other regions. These cancers are diagnosed in younger patients, are more aggressive clinically and don't respond as well to current treatments, which include chemotherapy and targeted systemic treatments.

Compared with most other forms of liver cancer, HBV-HCC from patients of African descent is relatively understudied, so little is known about its clinical behavior, its response to treatment and the genetic basis for these characteristics. Recent preliminary data have suggested that HBV-HCC may be more responsive to immunotherapy than are cancers associated with other forms of liver disease.

This proposal in the Developmental Research Program of the Mayo Clinic Hepatobiliary SPORE is studying HBV-HCC samples from people of African descent to characterize genetic mutations and gene activity to see if they are different from HBV-HCC from Asia and HCC associated with other liver diseases that have been extensively studied already. We are looking at genes that may explain the more aggressive tumor behavior and why these tumors don't respond as well to treatment. Finally, we are looking at mutation patterns that may help us understand whether HBV-HCC could respond to immunotherapy.

Abstract

Head and shoulders photograph of Sean P. Cleary, M.D.

Sean P. Cleary, M.D.
2021-2022 Awardee

The majority of hepatocellular carcinoma cases develop in patients with underlying liver disease due to viral infection, alcohol abuse or fat infiltration. Treatment decisions in HCC are made based on tumor size, tumor number and severity of underlying liver disease. Despite significant heterogeneity in the predisposing etiology and genetics of HCC, biomarker-based or etiology-based stratification of patients based on disease biology or anticipated response to therapy are lacking.

Hepatitis B virus is an oncogenic virus that is the most common cause of hepatocellular carcinoma, with high prevalence rates of chronic infection in Africa and Asia. Based on age of onset, presentation and clinical outcomes, HBV-associated HCC in Africa and Asia is more aggressive than are cancers in other regions, indicating significant variations in viral genotypes, cancer risk and disease biology across regions. Exposure to environmental risk factors, including several carcinogens linked to HCC risk, are observed in different regions. Recent data have suggested potentially clinically significant differences in response to systemic therapy between regions and disease etiologies. To date, patients of African origin have been underrepresented in clinical trials and multi-omic studies of HCC. In addition, limitations in existing sequencing technologies have prevented a full assessment of viral integrations and large genomic rearrangements seen in HBV-associated HCC.

This application proposes a comprehensive multidimensional assessment of HBV-HCC in Asian and West and East African communities to elucidate the key host factors that determine risk of HBV-induced HCC.

In Aim 1, we are performing a genomic and transcriptomic assessment of a limited cohort of HCC samples from native and immigrant people of African ethnicity. In Aim 2, we are using long-read sequencing technology (PacBIO sequencing), to study tumor samples from patients from Africa and Asia with HBV-HCC. This will allow us to evaluate HBV integrations and large genomic rearrangements and HBV sequence variants that may be associated with cancer risk or influence on gene expression in tumors. Subsequent work is then comparing African HBV-HCC expression and somatic mutation data of HBV-HCC from patients of Asian and Caucasian descent and of differing disease etiologies (HCV-HCC and nonalcoholic fatty liver disease-HCC) available through the TCGA and Hepatobiliary SPORE databases. This aim investigates the specific and unique genomic features and gene expression patterns that correlate with clinical phenotype, viral etiology and region, including specific characterization of mutations associated with environmental carcinogens.

Genomic and gene expression data are being compared to identify molecular mechanisms and pathways specific for ethnicity and poor oncologic outcomes. Transcriptional activation of key genes and pathways are being interrogated for potential insights into susceptibility to multikinase inhibitors and potential novel targets for therapy. Mutation burden, neoantigen load, and PD-1, PDL-1 and CT8 expression are being assessed to identify tumor subgroups and biomarkers to predict response to immunotherapy.

This project is expected to generate important preliminary data about patients of African descent with HBV-HCC and provide key insights into etiologic and regional differences in the molecular characteristics of HCC that may influence response to multikinase agents and immunotherapy. This project leverages important Hepatobiliary SPORE resources, including the biospecimen repository and core services in the bioinformatics group. The insights gained through this work would provide a compelling foundation for further investigation of molecular determinants of hepatocellular carcinoma biology and treatment response.