Hereditary Genetics of Hepatocellular Carcinoma

点击翻译按钮获取中文摘要

Project Summary Hepatocellular Carcinoma (HCC) is a devastating and prevalent cancer of the liver with high rates of mortality. Major risk factors include chronic viral infection (hepatitis B or C), fatty liver disease, alcohol use, and exposure to environmental toxins. An independent risk factor is a family history of HCC, which raises the risk by more than 2.5-fold. However, despite evidence of familial risk, the inherited component remains unknown. It also remains unexplored whether inherited gene variants play a pathogenic role in HCC development, or whether they could be used to guide treatment with targeted therapies. We have pioneered an investigation into inherited (i.e. germline) genetic factors associated with HCC. We have completed a pilot analysis of 217 patients with HCC prospectively enrolled from our medical center for clinical-grade multigene panel genetic testing. We have captured details about their personal and family cancer history, risk factors, and outcomes. In our pilot analysis, we found a surprisingly high rate of pathogenic germline variants in cancer-associated genes in patients with HCC, including numerous pathogenic and likely pathogenic variants in genes required for homologous repair, DNA damage response (HR-DDR). We hypothesize that inherited loss-of-function variants in specific genes are enriched in HCC, and that carriers can be treated with targeted therapies. In Aim 1, we will conduct genetic association studies that are powered to detect clinically meaningful germline variants linked to HCC, and we will examine predictors of hereditary cancer syndromes in HCC including age of onset and family history of cancer. In Aim 2, we will explore the mechanism of HCC arising from defects in HR-DDR genes, and determine the implications for targeted therapies. These innovative studies of the hereditary genetics of HCC have the potential to personalize therapies for the subset of patients with hereditary cancer syndromes. We have assembled a team of experts in HCC, hereditary genetics, and animal models to complete this investigation. This study has the potential to impact on the care of patients with HCC in the US and worldwide.