Hereditary Genetics of Hepatocellular Carcinoma

项目总结

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. A family history of HCC raises the risk by more than 2.5-fold. The parent R01 grant will conduct genetic association studies that are powered to detect clinically meaningful germline variants linked to HCC, and will examine predictors of hereditary cancer syndromes in HCC including age of onset and family history of cancer. It also explores the mechanism of HCC arising from defects in HR-DDR genes, and will determine the implications for targeted therapies. In this Diversity Supplement, we request additional funding to support the thesis work for the graduate trainee. Her proposed work falls within the scope of the parent grant. In this project, we have completed a CRISPR activation screen in mice livers of genes that are upregulated in human HCC. We found that upregulated Clk2 expression can drive the development of HCC. CLK2 is a gene involved in splicing that has been found to be a driver in a number of solid cancers, and early work with inhibitors looks promising. We hypothesize that CLK2 promotes HCC via the WNT/β-catenin pathway and that CLK2 inhibitors could prevent HCC development. We propose to address this hypothesis with the following aims: Aim 1 will investigate whether CLK2 is required for tumorigenesis by performing pharmacological and CRISPR targeting of this genes in HCC cell lines and in vivo models; Aim 2 will examine whether the mechanism of CLK2 in driving tumorigenesis is by binding SRSF1 and SRSF3 to influence alternative splicing. These innovative studies of the genetics of HCC have the potential to personalize therapies for the subset of patients with HCC. The mentee will have a mentorship 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.