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.

项目摘要肝细胞癌（HCC）是肝脏的毁灭性癌症，死亡率高。主要危险因素包括慢性病毒感染（乙型肝炎或C），脂肪肝病，酒精和暴露到环境毒素。独立的危险因素是一级亲戚的HCC家族史，该历史将风险提高了2.5倍以上。但是，尽管有家族风险的证据，但与遗传癌的联系很少已经确定了综合征。尚不清楚遗传基因突变在 HCC开发，或者是否可以用于指导治疗。我们已经开创了调查遗传（即种系）与HCC相关的遗传因素。我们有未来招收了220名患者 HCC来自我们的临床级基因检测中心。我们记录了他们个人的细节以及家庭癌症病史，危险因素和结果。在我们的试点分析中，我们发现 HCC患者的癌症相关基因中的致病性系突变，包括众多突变在同源修复（HR-DDR）所需的DNA损伤反应基因中。在AIM 1中，我们将进行遗传协会研究有动力检测与HCC相关的临床意义种系突变，我们将检查遗传性癌症综合征在早期发作HCC的人中是否更常见或有癌症家族史。在AIM 2中，我们将探讨HR-缺陷引起的HCC机制 DDR基因，并确定对靶向疗法的影响。这些对世袭的独特研究 HCC的遗传学有可能个性化遗传癌患者子集的疗法综合征。我们已经组建了一个HCC，遗传遗传学和动物模型的专家团队，以完成这项调查。这项研究有可能塑造美国和全球HCC患者的护理。