Hereditary Genetics of Hepatocellular Carcinoma

肝细胞癌的遗传遗传学

• 批准号: 10598810
• 负责人: Kirk J Wangensteen
• 金额: $ 8.1万
• 依托单位: MAYO CLINIC ROCHESTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-01 至 2027-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10598810
• 关键词: Address; Age of Onset; Alcohol consumption; Alternative Splicing; Animal Model; Automobile Driving; Binding; CRISPR-mediated transcriptional activation; Chronic; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; DDR1 gene; Defect; Development; Environmental Risk Factor; Exposure to; Family Cancer History; Family history of; Funding; Genes; Genetic; Genetic Models; Genetic study; Grant; Hepatitis B; Hepatitis C; Hereditary Neoplastic Syndromes; Human; Inherited; Investigation; Link; Liver; Malignant Neoplasms; Malignant neoplasm of liver; Mentorship; Mus; Parents; Pathway interactions; Patient Care; Pharmacology; Primary carcinoma of the liver cells; RNA Splicing; Risk; Risk Factors; Solid; Toxic Environmental Substances; Training Support; Variant; Virus Diseases; Work; beta catenin; falls; fatty liver disease; genetic association; graduate student; hepatocellular carcinoma cell line; in vivo Model; inhibitor; innovation; mortality; parent grant; parent project; patient subsets; personalized medicine; prevent; targeted treatment; tumorigenesis

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.

项目概要 肝细胞癌（HCC）是一种破坏性且普遍的肝癌，死亡率很高。 主要危险因素包括慢性病毒感染（乙型或丙型肝炎）、脂肪肝、饮酒和暴露 HCC 家族史会使风险增加 2.5 倍以上。 进行遗传关联研究，以检测与相关的具有临床意义的种系变异 HCC，并将检查 HCC 遗传性癌症综合征的预测因素，包括发病年龄和家庭 它还探讨了HR-DDR基因缺陷引起HCC的机制，并将 确定对靶向治疗的影响 在本多样性补充中，我们请求额外的资金 支持研究生实习生的论文工作属于家长资助的范围。 在这个项目中，我们已经完成了对小鼠肝脏中上调基因的 CRISPR 激活筛选 我们发现上调的 Clk2 表达可以驱动 HCC 的发展。 参与剪接已被发现是许多实体癌的驱动因素，以及抑制剂的早期研究 我们认为 CLK2 通过 WNT/β-连环蛋白途径促进 HCC，并且 CLK2 看起来很有希望。 我们建议通过以下目标来解决这一假设： 1将通过药理学和CRISPR研究CLK2是否是肿瘤发生所必需的 在 HCC 细胞系和体内模型中靶向该基因；目标 2 将检查 CLK2 的机制是否有效 驱动肿瘤发生的机制是通过结合 SRSF1 和 SRSF3 来影响这些创新剪接。 HCC 遗传学研究有可能为部分 HCC 患者提供个性化治疗。 学员将拥有一个由 HCC、遗传遗传学和动物模型专家组成的指导团队来完成 这项研究有可能对美国和全世界 HCC 患者的护理产生影响。