Hereditary Genetics of Hepatocellular Carcinoma

项目摘要 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。一个独立的风险因素是肝癌的家族史，这会使风险增加超过 2.5倍。然而，尽管有家族性风险的证据，但遗传成分仍然未知。它也保留了下来 未探索遗传基因变异是否在肝细胞癌的发生中起致病作用，或者它们是否可以 用于指导靶向治疗。我们率先对继承的(即 生殖系)与肝细胞癌相关的遗传因素。我们已经完成了217例肝细胞癌患者的初步分析 预期从我们医学中心登记参加临床级多基因小组基因检测。我们有 获取有关他们的个人和家庭癌症病史、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，癌症相关基因的致病胚系变异率高得惊人 肝细胞癌，包括同源修复所需基因中的许多致病和可能致病变异， DNA损伤反应(HR-DDR)。我们假设在特定基因中遗传的功能丧失变异是 富含肝细胞癌，携带者可以用靶向治疗。在目标1中，我们将进行遗传 有能力检测与肝癌相关的具有临床意义的生殖系变异的协会研究，我们将 检查肝细胞癌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，我们将探讨由HR-DDR基因缺陷引起的肝细胞癌的机制，并确定 对靶向治疗的影响。这些关于肝细胞癌遗传遗传学的创新性研究具有潜力 为遗传性癌症综合征患者亚群提供个性化治疗。我们已经组建了一支 由肝细胞癌、遗传遗传学和动物模型专家组成的团队完成这项调查。这项研究有 对美国和世界各地肝细胞癌患者护理的潜在影响。

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.