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

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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.