Hereditary Genetics of Hepatocellular Carcinoma

肝细胞癌的遗传遗传学

基本信息

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
项目类别：
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

项目摘要

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。