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.

项目总结 肝细胞癌是一种严重危害人类健康的常见肝癌，死亡率高。 主要危险因素包括慢性病毒感染(乙肝或丙型肝炎)、脂肪肝、饮酒和接触 环境毒素。一个独立的危险因素是肝细胞癌的一级亲属的家族史， 使风险增加2.5倍以上。然而，尽管有家族性风险的证据，但很少与遗传性癌症有关 症状已经被识别出来。目前也不清楚遗传基因突变是否起到致病作用。 肝癌的发展，或者它们是否可以被用来指导治疗。我们已经率先调查了 与肝细胞癌相关的遗传性(即生殖系)遗传因素。我们前瞻性地招募了220名患有 从我们的医学中心进行临床级基因检测。我们已经记录了他们个人的详细情况 以及家族癌症病史、危险因素和结果。在我们的试点分析中，我们发现令人惊讶的高比率 肝细胞癌患者肿瘤相关基因的致病胚系突变，包括大量突变 同源修复所需的DNA损伤反应基因(HR-DDR)。在目标1中，我们将进行一项基因 一项旨在检测与肝细胞癌相关的具有临床意义的种系突变的协会研究，我们将 检查遗传性癌症综合征是否在早期发病的肝癌患者中更为常见 或者有癌症家族史。在目标2中，我们将探讨由HR-1缺陷引起的肝癌的机制。 DDR基因，并确定靶向治疗的含义。这些关于遗传性的独特研究 肝癌的遗传学有可能使遗传性癌症患者的个人化治疗成为可能 综合症。我们已经组建了一个由肝细胞癌、遗传遗传学和动物模型专家组成的团队来完成 这次调查。这项研究有可能对美国和世界各地的肝癌患者的护理产生影响。