Hereditary Genetics of Hepatocellular Carcinoma

项目摘要 肝细胞癌（HCC）是一种毁灭性的和普遍的肝癌，死亡率高。 主要的风险因素包括慢性病毒感染（乙型或丙型肝炎B）、脂肪肝、饮酒和暴露 环境毒素。一个独立的危险因素是一级亲属有HCC家族史， 风险会增加2.5倍然而，尽管有证据表明有家族风险，但与遗传性癌症的联系很少。 综合征已被确认。遗传性基因突变是否在疾病中起致病作用也不清楚。 HCC的发展，或者它们是否可以用来指导治疗。我们率先调查了 与HCC相关的遗传（即生殖系）遗传因素。我们前瞻性招募了220名患者， 我们医疗中心的HCC进行临床级基因检测。我们已经记录了他们的个人细节 家族癌症史、危险因素和结果。在我们的试点分析中，我们发现了一个令人惊讶的高比率， HCC患者中癌症相关基因的致病性生殖系突变，包括许多突变 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 一项关联研究，能够检测与HCC相关的有临床意义的生殖系突变，我们将 检查遗传性癌症综合征是否在早发性肝癌患者中更常见 或者有癌症家族史在目标2中，我们将探索由HR缺陷引起的HCC的机制- DDR基因，并确定对靶向治疗的影响。这些关于遗传性的独特研究 HCC的遗传学有可能为遗传性癌症患者的子集提供个性化治疗 综合征我们组建了一个由HCC、遗传遗传学和动物模型专家组成的团队， 这次调查这项研究有可能塑造美国和全球HCC患者的护理。

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.