Identification of new rare germline variants predisposing to alcohol-related hepatocellular carcinoma

鉴定易患酒精相关性肝细胞癌的新罕见种系变异

• 批准号: 504473047
• 负责人: Dr. Louisa Stern
• 金额: --
• 依托单位: Klinik und Poliklinik für Allgemein-, Viszeral- und Thoraxchirurgie
• 依托单位国家: 德国
• 项目类别: WBP Fellowship
• 资助国家: 德国
• 项目状态: 未结题
• 来源: https://gepris.dfg.de/gepris/projekt/504473047?language=en
• 关键词: Identification; new; rare; germline; variants

Hepatocellular carcinoma (HCC) is a heterogeneous tumor of which more than 90% are believed to develop in a cirrhotic liver on the background of chronic liver disease. In Western countries, alcohol abuse and Hepatitis C (HCV) are the most frequent causes of HCC, whereas in sub-Saharan Africa Hepatitis B (HBC) is still the main risk factor. Another common etiological factor rapidly gaining importance due to the growing epidemic of obesity is non-alcoholic steatohepatitis (NASH). The role of heritability in HCC remains largely unknown until now. However, familial aggregation found in case-control studies and analyses of cancer databases strongly indicates a hereditary component in liver cancer. Primary genetic factors might be among the reasons why only a subset of patients with liver cirrhosis develop HCCs. In order to ensure early diagnosis, a prerequisite for curative treatment, international guidelines recommend HCC screening in all patients with known cirrhosis. Risk-stratification for targeted screening is not available, yet. The aim of this research fellowship is to identify new rare and common germline variants in the coding region of the genome predisposing to ALD-HCC. In addition, constitutional variants that have previously been associated with susceptibility to HCC shall be validated in this cohort. Finally, the functional impact of all these variants and their underlying molecular mechanisms shall be assessed by studying interactions with somatic mutation profiles and correlations with clinicopathological parameters. Ultimately, the project is aimed at contributing to an algorithm for risk-stratified screening, surveillance, and treatment of HCCs based on the patients’ individual genetic profile. In addition, newly identified variants predisposing to HCC could also serve as novel targets for future therapeutic approaches. Since alcohol abuse is the most common etiological factor for HCC in Western Europe and is expected to gradually become the leading cause worldwide due to decreasing HBV and HCV infections, this study will mainly focus on patients with ALD-HCC of Caucasian origin. For this purpose, a systematic analysis of new rare and more common germline mutations in a discovery cohort of 210 ALD-HCC patients will be performed. An evaluation of molecular and functional consequences of the previously identified variants will be carried out. WES or WGS data are available for all HCC tumors- RNA sequencing and methylation analysis or reduced representation bisulfite sequencing are available for 80% and 50% of them. For validation, the most promising germline variants previously identified in the exploratory cohort will be resequenced in a replication cohort of 500 ALD-HCCs and control ALD patients without HCC.

肝细胞癌（HCC）是一种异质性肿瘤，其中超过90%被认为是在慢性肝病的背景下发生的。在西方国家，酒精滥用和丙型肝炎（HCV）是HCC最常见的原因，而在撒哈拉以南非洲，B型肝炎（HBC）仍然是主要的风险因素。另一个由于肥胖症的流行而迅速变得重要的常见病因是非酒精性脂肪性肝炎（NASH）。迄今为止，遗传性在HCC中的作用仍然很大程度上未知。然而，在病例对照研究和癌症数据库分析中发现的家族聚集性强烈表明肝癌的遗传成分。原发性遗传因素可能是只有一部分肝硬化患者发生HCC的原因之一。为了确保早期诊断，治愈性治疗的先决条件，国际指南建议在所有已知肝硬化患者中进行HCC筛查。针对性筛查的风险分层尚不可用。这项研究的目的是确定新的罕见和常见的种系变异的基因组编码区易感ALD-HCC。此外，应在该队列中验证先前与HCC易感性相关的体质变异。最后，所有这些变体的功能影响及其潜在的分子机制将通过研究与体细胞突变谱的相互作用以及与临床病理参数的相关性来评估。最终，该项目旨在根据患者的个体遗传特征，为HCC的风险分层筛查、监测和治疗算法做出贡献。此外，新发现的易患HCC的变异也可以作为未来治疗方法的新靶点。由于酒精滥用是西欧HCC最常见的病因，并且由于HBV和HCV感染的减少，预计将逐渐成为全球范围内的主要病因，因此本研究将主要关注白人ALD-HCC患者。为此，将在210例ALD-HCC患者的发现队列中对新的罕见和更常见的种系突变进行系统分析。将对先前鉴定的变体的分子和功能后果进行评价。WES或WGS数据可用于所有HCC肿瘤- RNA测序和甲基化分析或减少代表性亚硫酸氢盐测序可用于其中的80%和50%。为了验证，将在500例ALD-HCC和对照ALD患者（无HCC）的复制队列中对先前在探索性队列中鉴定的最有希望的生殖系变体进行重新测序。