Hereditary Genetics of Hepatocellular Carcinoma

肝细胞癌的遗传遗传学

基本信息

批准号：
10366233
负责人：
Kirk J Wangensteen
金额：
$ 17.79万
依托单位：
UNIVERSITY OF PENNSYLVANIA
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：
2022-02-01 至 2022-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10366233
关键词：
Address Age Age of Onset Alcohol consumption Alcohols Animal Model BRCA2 gene CHEK2 gene Candidate Disease Gene Chronic Clinical Confidence Intervals DNA Damage DNA Repair DNA Repair Gene 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 Genes Genetic Genetic Models Genetic Models for Cancer Genetic study Hepatitis B Hepatitis C Hereditary Neoplastic Syndromes Histologic Individual Inherited Institution Investigation Knowledge Link Liver neoplasms Loss of Heterozygosity MSH6 gene Malignant Neoplasms Malignant neoplasm of liver Medical center Odds Ratio Outcome PMS2 gene Pathogenesis Pathogenicity Patient Care Patients Pharmacotherapy Phenotype Pilot Projects Play Population Population Control Practice Guidelines Predisposition Primary carcinoma of the liver cells Proteins Recommendation Recording of previous events Risk Risk Factors Role Stains Susceptibility Gene Test Result Testing Toxic Environmental Substances Tumor Tissue Variant Virus Diseases base cancer cell cancer predisposition cancer risk carcinogenesis case control clinical center clinical practice clinically relevant early onset exome fatty liver disease gene function gene panel gene repair genetic association genetic panel test genetic risk factor genetic testing genetic variant genomic locus high risk homologous recombination improved inhibitor inhibitor therapy innovation liver cancer model loss of function mortality patient subsets personalized medicine prospective rare variant repaired 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, which raises the risk by more than 2.5-fold. However, despite evidence of familial risk, the inherited component remains unknown. It also remains unexplored whether inherited gene variants play a pathogenic role in HCC development, or whether they could be used to guide treatment with targeted therapies. We have pioneered an investigation into inherited (i.e. germline) genetic factors associated with HCC. We have completed a pilot analysis of 217 patients with HCC prospectively enrolled from our medical center for clinical-grade multigene panel genetic testing. We have captured details about their personal and family cancer history, risk factors, and outcomes. In our pilot analysis, we found a surprisingly high rate of pathogenic germline variants in cancer-associated genes in patients with HCC, including numerous pathogenic and likely pathogenic variants in genes required for homologous repair, DNA damage response (HR-DDR). We hypothesize that inherited loss-of-function variants in specific genes are enriched in HCC, and that carriers can be treated with targeted therapies. In Aim 1, we will conduct genetic association studies that are powered to detect clinically meaningful germline variants linked to HCC, and we will examine predictors of hereditary cancer syndromes in HCC including age of onset and 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 innovative 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 impact on 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 HCC 家族史，这会使风险增加超过 2.5倍。然而，尽管有证据表明存在家族风险，但遗传因素仍然未知。也还保留着尚未探索遗传基因变异是否在 HCC 发展中发挥致病作用，或者它们是否可以用于指导靶向治疗。我们率先对遗传（即遗传）进行了调查。种系）与 HCC 相关的遗传因素。我们已经完成了对 217 名 HCC 患者的初步分析前瞻性地从我们的医疗中心招募进行临床级多基因组基因检测。我们有获取有关他们个人和家族癌症史、风险因素和结果的详细信息。在我们的试点分析中，我们发现，在患有癌症的患者中，癌症相关基因中致病性种系变异的发生率惊人地高。 HCC，包括同源修复所需基因中的许多致病性和可能致病性变异， DNA 损伤反应 (HR-DDR)。我们假设特定基因中的遗传性功能丧失变异是富含 HCC，携带者可以通过靶向治疗进行治疗。在目标1中，我们将进行遗传关联研究能够检测与 HCC 相关的具有临床意义的种系变异，我们将检查 HCC 遗传性癌症综合征的预测因素，包括发病年龄和癌症家族史。在目标2中，我们将探讨HR-DDR基因缺陷引起HCC的机制，并确定HR-DDR基因缺陷引起HCC的机制。对靶向治疗的影响。这些关于 HCC 遗传遗传学的创新研究具有潜力为患有遗传性癌症综合征的患者提供个性化治疗。我们组装了一个 HCC、遗传遗传学和动物模型专家团队完成了这项研究。这项研究有对美国和全球 HCC 患者护理的潜在影响。