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Mechanisms underlying hepatocellular carcinoma pathogenesis and impact of co-morbidities.

Periodic Reporting for period 3 - HEP-CAR (Mechanisms underlying hepatocellular carcinoma pathogenesis and impact of co-morbidities.)

Reporting period: 2019-01-01 to 2019-12-31

Hepatocellular carcinoma (HCC) is the second most common cause for cancer related death in the world, with an estimated 750,000 new cases and 695,000 deaths per year. WHO estimate that HCC is responsible for around 47,000 deaths per year in Europe. HCC develops from chronic and progressive liver injury that arises via an array of insults to the liver including obesity associated non-steatohepatitis (NASH); alcohol-related steatohepatitis (ASH), chronic hepatitis B and C virus (HBV/HCV) infection. These co-morbidities impact on both diagnosis and treatment response, however, they are not currently considered in patient management guidelines. Recent health economic studies in Europe have estimated the incidence and mortality rates of HCC of 65,000 and 60,240 cases. In almost all populations, males have higher liver cancer rates than females, with male:female ratios usually averaging between 2:1 and 4:1. Given prevailing demographic and life expectancy trends, the number of HCC patients is expected to be as many as 78,000 in 2020. Studies indicate that the number of HCC related hospitalizations are increasing compared with two decades ago, causing significant direct costs. Thus, HCC is a cause of a significant and increasing overall burden for health systems and society overall and the increasing number of individuals with HCC may have major public health and economic implications.
Given the limited efficacy of current treatments and the huge social implications of HCC progression, this highlights the urgent need to define common and co-morbidity specific pathways and associated bio-markers for patient stratification to improve diagnosis and therapy. The HEP-CAR consortium aimed to extend and integrate the pathophysiological knowledge on HCC to determine the impact of co-morbidities on the prevention, diagnosis and treatment of HCC. Our goal was to develop and validate informed management strategies based on the major co-morbidities associated with HCC progression in the European population. HEP-CAR employed the multidisciplinary skills of selected European partners with expertise in liver disease and who have well characterised HCC cohorts and excellent resources to address the objectives of the project.

The summary of achievements regarding the overall HEP-CAR objectives are summarised below:
• Define host pathways associated with HCC co-morbidities including non-alcoholic steatohepatitis (NASH), chronic hepatitis B and C virus (HBV/HCV) infections. In general we found host pathways altered in HCC independent of the co-morbidity as well as co-morbidity-specific alterations
• Develop clinical tools that will personalize prevention and treatment of HCC patients. We identified phosphopeptides as novel HCC-associated antigens recognized by CD8+ T cells that may emerge as a promising novel tool in personalized HCC treatment expecially since the phosphoproteome is affected by co-morbidity.
• Guide future strategies to prevent, diagnose, and treat HCC in Europe. We made several steps to deliver new data relevant for HCC classification and treatment

Taken together, the obtained results have clearly paved the way for translational exploitation.
Our main focus during the four-year funding period of the HEP-CAR consortium was on the analysis of molecular, viral and immune pathways and their contribution to the development of HCC. By studying genomic alterations in large HCC sample collections we identified that the telomerase as well as the ß-catenin pathway are mainly altered independent of the co-morbidity except for NASH. In case of NASH two driver candidate genes were determined that promote HCC development. Furthermore, our analyses revealed that there are also HCV-HCC-specific alterations in signalling pathways like e.g. MAP kinase signalling or DNA repair. In addition we identified a hypoxia-related gene signature and an immune-mediated cancer field (ICF) signature as biomarkers allowing the clinical classification of HCC and that are associated with outcomes. Finally, with respect to novel immunotherapeutic approaches we identified a large number of phosphopeptides to be novel HCC-associated antigens that are targeted by CD8+ T cells and represent a potentially novel tool in the development of therapeutic strategies. Of note, we could show that phosphoproteomes are diversely affected by different co-morbidities like HBV and HCV infection and thus representing co-morbidity specific pathways in HCC development and progression.
HEP-CAR moved beyond current state of the art by defining the molecular pathways associated with HCC co-morbidities, specifically NASH, chronic HBV and HCV infection and thus allowing us to personalize health policy and advice. HEP-CAR identified biomarkers that have innovation potential, possibly leading to the development of novel screening tools to allow individuals and clinicians to focus on lifestyle (e.g. NASH) or specific therapeutic interventions (e.g. HBV, HCV) to prevent disease progression.
In summary, the identification of co-morbidity specific or common drivers that associate with HCC progression or diagnosis are the first steps towards translation into algorithms to plan and evaluate stratified interventions to prevent and manage HCC in the future. Such advances have the potential to impact on morbidity, mortality and costs to the European population caused by HCC.

Since the beginning of the project, several dissemination activities have been performed to enhance visibility of the consortium and of the project, mainly for informing the scientific community and stakeholders and for communicating the value of the research funded by the European Community through H2020. These have included: development of a project website, development of project information material (i.e. logo, brochure), participation of HEP-CAR scientists at scientific events, publications of results in peer-reviewed high impact journals.
HEP-CAR will move beyond current state of the art by defining the molecular pathways associated with HCC co-morbidities, specifically NASH, chronic HBV and HCV infection and thus allowing us to personalize health policy and advice. HEP-CAR will identify biomarkers that have innovation potential, possibly leading to the development of novel screening tools to allow individuals and clinicians to focus on lifestyle (e.g. NASH) or specific therapeutic interventions (e.g. HBV, HCV) to prevent disease progression.
In summary, the identification co-morbidity specific or common drivers that associate with HCC progression or diagnosis will provide algorithms to plan and evaluate stratified interventions to prevent and manage HCC in the future. Such advances have the potential to impact on morbidity, mortality and costs to the European population caused by HCC.
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Management structure of HEP-CAR project
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Graphical presentation of the project Workpackages showing how they inter-relate
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HEP-CAR Consortium