Military Relevance Focus Areas: Military-relevant risk factors associated with cancer; Gaps in cancer prevention, screening, diagnosis, and treatment.

Scientific Objectives: We aim to develop an innovative experimental system to quickly identify molecular drivers of liver cancer development after clearance of oncogenic hepatitis C virus (HCV) variants, identify therapies to prevent liver cancer, and create a clinical lab test to find patients who achieve cure of oncogenic HCV infection but still at risk of cancer and need cancer prevention therapy.

Rationale: In the US, HCV is the major cause of liver cancer, the second leading cause of cancer death worldwide and the most rapidly and only increasing cause of cancer death in the US. Although recently emerging anti-HCV drugs can clear HCV at a very high rate, it has become evident that HCV cure does not eliminate the risk of liver cancer at least over a decade. Therefore, biomarkers to predict who are at risk of cancer after HCV cure and cancer preventive therapies for them are urgently needed. In addition, certain HCV variants are clinically known to be associated with >four-fold increase of liver cancer risk even after viral eradication, clearly indicating urgent necessity to identify cancer prevention strategy for the oncogenic HCV variants.

Ultimate Applicability of the Research: Individuals who successfully achieve cure of oncogenic HCV variants but are still at risk of cancer will benefit from the research by being identified as high-priority patients for cancer prevention care. The research will yield clinical lab test to predict liver cancer risk after cure of oncogenic HCV variants and enable fast-track cancer prevention drug discovery ready for clinical use. The research will yield immediately clinically applicable products, namely candidate cancer prevention drugs and clinical test of cancer risk. Also, the experimental system developed in the study will enable further exploration of better cancer prevention therapies in an innovatively convenient way. The research will open the door to a new paradigm, viral strain-specific molecular cancer prevention, which is widely applicable to other virus-induced cancers, and break the status quo.

Relevance to Military Beneficiaries: HCV infection in US Veterans is more than three-fold frequent than in the general US population. Over the past decade, the number of Veterans with HCV-related liver cancer has increased nine-fold. Even with the recently developed highly effective anti-HCV drugs, it is predicted that Veterans who develop liver cancer will keep increasing in the next decades, clearly indicating military relevance of HCV-induced liver cancer.