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.

项目摘要 肝细胞癌（HCC）是一种毁灭性的、普遍存在的肝脏癌症，死亡率很高。 主要的风险因素包括慢性病毒感染（乙型或丙型肝炎B）、脂肪肝、饮酒和暴露 环境毒素。HCC家族史使风险增加2.5倍以上。父R 01补助金将 进行遗传关联研究，以检测与以下疾病相关的具有临床意义的生殖系变异： 并将检查HCC中遗传性癌症综合征的预测因素，包括发病年龄和家族史 癌症史。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。在此多样性补充中，我们要求额外的资金， 支持毕业实习生的论文工作。她提议的工作福尔斯属于父母补助金的范围。在 在这个项目中，我们已经完成了小鼠肝脏中基因的CRISPR激活筛选，这些基因在小鼠肝脏中的表达上调， 人HCC。我们发现Clk 2表达上调可以驱动HCC的发展。CLK 2是一个基因 参与剪接，已被发现是许多实体癌的驱动因素， 看起来很有希望我们假设，CLK 2通过WNT/β-catenin途径促进HCC，而CLK 2通过WNT/β-catenin途径促进HCC。 抑制剂可以防止HCC的发展。我们建议解决这一假设与以下目标：目的 1将通过进行药理学和CRISPR研究来研究肿瘤发生是否需要CLK 2。 在HCC细胞系和体内模型中靶向该基因;目的2将研究CLK 2的机制是否 是通过结合SRSF 1和SRSF 3来影响选择性剪接。这些创新 对HCC遗传学的研究有可能为HCC患者的亚群提供个性化治疗。 学员将有一个由HCC、遗传遗传学和动物模型专家组成的导师团队来完成 这次调查这项研究有可能影响美国和全球HCC患者的护理。