Hereditary Genetics of Hepatocellular Carcinoma

肝细胞癌的遗传遗传学

• 批准号: 10632953
• 负责人: Kirk J Wangensteen
• 金额: $ 51.03万
• 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/10632953
• 关键词: Address; Age; Age of Onset; Alcohol consumption; Alcohols; American; Animal Model; BRCA2 gene; CHEK2 gene; Chronic; Cirrhosis; Clinical; Confidence Intervals; DNA Damage; DNA Repair; DNA Repair Gene; DNA Sequence Alteration; Data; Defect; Demographic Factors; Development; Diagnosis; Enrollment; Environmental Risk Factor; Exposure to; FANCD2 protein; Family; Family Cancer History; Family history of; Family member; Fanconi Anemia Complementation Group A Protein; Fatty Liver; Fibrinogen; First Degree Relative; Gene Expression; Gene Mutation; Genes; Genetic; Genetic Models; Germ-Line Mutation; Goals; Hepatitis B; Hepatitis C; Hereditary Malignant Neoplasm; Hereditary Neoplastic Syndromes; Histologic; Individual; Inherited; Institution; Investigation; Link; Liver neoplasms; Loss of Heterozygosity; MSH6 gene; Malignant Neoplasms; Malignant neoplasm of liver; Medical Genetics; Medical center; Mutation; Odds Ratio; Oncogenes; Outcome; PMS2 gene; Pathogenesis; Pathogenicity; Patient Care; Patients; Persons; Pharmacotherapy; Pilot Projects; Play; Population; Population Control; Predisposition; Primary carcinoma of the liver cells; Proteins; Race; Recording of previous events; Risk; Risk Factors; Role; Sampling; Shapes; Stains; Test Result; Testing; Time; Toxic Environmental Substances; Tumor Tissue; Venous blood sampling; Virus Diseases; base; cancer risk; cancer type; carcinogenesis; case control; clinical center; early onset; exome sequencing; fatty liver disease; gene function; gene panel; gene repair; genetic association; genetic testing; genomic locus; high risk; homologous recombination; inhibitor; liver cancer model; loss of function; medical schools; mortality; patient subsets; personalized medicine; precision drugs; prospective; recruit; repaired; research clinical testing; response; targeted treatment; treatment strategy; tumor

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 in a first degree relative, which raises the risk by more than 2.5-fold. However, despite evidence of familial risk, few links to hereditary cancer syndromes have been identified. It is also not clear whether inherited gene mutations play a pathogenic role in HCC development, or whether they could be used to guide treatment. We have pioneered an investigation into inherited (i.e. germline) genetic factors associated with HCC. We have prospectively enrolled 220 patients with HCC from our medical center for clinical-grade genetic testing. We have recorded the details of their personal and family cancer history, risk factors, and outcomes. In our pilot analysis, we found a surprisingly high rate of pathogenic germline mutations in cancer-associated genes in patients with HCC, including numerous mutations in DNA damage response genes required for homologous repair (HR-DDR). In Aim 1, we will conduct a genetic association study that is powered to detect clinically meaningful germline mutations linked to HCC, and we will examine whether hereditary cancer syndromes are more common in persons who developed early onset HCC or have a 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 unique 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 shape 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 对环境毒素。一个独立的危险因素是一级亲属有 HCC 家族史，其中 风险增加2.5倍以上。然而，尽管有证据表明存在家族风险，但与遗传性癌症的联系很少 综合症已被确定。目前还不清楚遗传性基因突变是否在疾病中发挥致病作用。 HCC 的发展，或者它们是否可以用来指导治疗。我们率先开展了一项调查 与 HCC 相关的遗传（即种系）遗传因素。我们前瞻性地招募了 220 名患有以下疾病的患者： 来自我们医疗中心的 HCC 临床级基因检测。我们已经记录了他们的个人详细信息 以及家族癌症史、危险因素和结果。在我们的试点分析中，我们发现了惊人的高比率 HCC 患者癌症相关基因的致病性种系突变，包括多种突变 同源修复所需的 DNA 损伤反应基因 (HR-DDR)。在目标 1 中，我们将进行遗传 关联研究旨在检测与 HCC 相关的具有临床意义的种系突变，我们将 检查遗传性癌症综合征在早发性 HCC 患者中是否更常见 或有癌症家族史。在目标 2 中，我们将探讨 HR 缺陷引起 HCC 的机制。 DDR 基因，并确定对靶向治疗的影响。这些独特的遗传研究 HCC 遗传学有可能为遗传性癌症患者提供个性化治疗 综合症。我们组建了 HCC、遗传遗传学和动物模型方面的专家团队来完成 这项调查。这项研究有可能影响美国和全世界 HCC 患者的护理。