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Systematic evaluation of the host genetics of alcohol-associated hepatocellular carcinoma

English title Systematic evaluation of the host genetics of alcohol-associated hepatocellular carcinoma
Applicant Stickel Felix
Number 169196
Funding scheme Project funding
Research institution Klinik für Gastroenterologie und Hepatologie Departement Innere Medizin Universitätsspital Zürich
Institution of higher education University of Zurich - ZH
Main discipline Clinical Cancer Research
Start/End 01.01.2017 - 31.12.2020
Approved amount 525'000.00
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All Disciplines (3)

Discipline
Clinical Cancer Research
Pathophysiology
Experimental Cancer Research

Keywords (3)

genome-wide scanning; genetic risk factor; PNPLA3

Lay Summary (German)

Lead
Genetisches Risiko bei alkoholbedingten Leberkrebs
Lay summary

Das Leberzellkarzinom (Leberzellkrebs) ist eine Komplikation der alkoholbedingten Leberzirrhose und nimmt weltweit zu. Der Hauptrisikofaktor für ein Leberzellkarzinom ist eine Leberzirrhose und es entwickelt etwa 10% der Patienten mit Leberzirrhose binnen 5 Jahren einen solchen Tumor. Neben Geschlecht, Übergewicht und Diabetes ist ein genetischer Faktor namens PNPLA3 mit einem erhöhten Risiko eines Leberkrebses assoziiert.

Unser Projekt hat folgende Ziele: 1. Identifikation von genetischen Faktoren im menschlichen Erbgut, die mit einen Leberkrebsrisiko vergesellschaftet sind mittels genomweiter Fall-Kontrollstudie (GWAS); 2. Klärung der funktionellen Rolle des genetischen Risikofaktors PNPLA3 in der Entstehung des Leberkrebses durch Versuche mit Mäuse und Zelllinien mit genetisch verändertem PNPLA3-Gen; 3. Untersuchung von 1-(2) weiteren bislang noch nicht bekannten genetischen Faktoren wie unter 2. beschrieben. Diese sollen durch die GWAS ermittelt werden.

In der GWAS sollen Patienten mit Alkoholzirrhose und Leberkrebs mit Alkoholzirrhosepatienten ohne Leberkrebs verglichen werden und die dabei identifizierten genetischen Risikofaktoren anschliessend in einer separaten Gruppe von Fällen und Kontrollen bestätigt werden. Experimentell sollen Zellen bzw. Mäuse eingesetzt werden, die bezüglich des PNPLA3-Gens genetisch verändert wurden. Dabei kommt ein Tiermodell zum Einsatz, welches in den Mäusen Leberkrebs hervorruft. Dabei werden in Zellkultur und Tierexperiment biologische Vorgänge, die typisch für Krebswachstum sind, unter den Bedingungen der genetischen Modifikation untersucht.

Unsere Studie kann neue genetische Risikofaktoren für Leberkrebs identifizieren und deren Rolle in der Leberkrebsentstehung klären. Die Identifikation solcher Gene und funktionelle Charakterisierung würde einen wesentlichen Beitrag zum besseren Verständnis der Leberkrebsentstehung liefern und potenziell neue präventive und therapeutische Strategien eröffnen.

Direct link to Lay Summary Last update: 01.12.2016

Responsible applicant and co-applicants

Employees

Publications

Publication
Combined effects of PNPLA3, TM6SF2 and HSD17B13 variants on severity of biopsy-proven non-alcoholic fatty liver disease
Paternostro Rafael, Staufer Katharina, Traussnigg Stefan, Stättermayer Albert-Friedrich, Halilbasic Emina, Keritam Omar, Meyer Elias L., Stift Judith, Wrba Fritz, Sipos Bence, Canbay Ali, Schlattjan Martin, Aigner Elmar, Datz Christian, Stickel Felix, Schafmayer Clemens, Hampe Jochen, Buch Stephan, Prager Gerhard, Munda Petra, Mandorfer Mattias, Ferenci Peter, Trauner Michael (2021), Combined effects of PNPLA3, TM6SF2 and HSD17B13 variants on severity of biopsy-proven non-alcoholic fatty liver disease, in Hepatology International, 10(6), 115-122.
The rs738409 G Allele in PNPLA3 Is Associated With a Reduced Risk of COVID-19 Mortality and Hospitalization
Innes Hamish, Buch Stephan, Barnes Eleanor, Hampe Jochen, Marjot Thomas, Stickel Felix (2021), The rs738409 G Allele in PNPLA3 Is Associated With a Reduced Risk of COVID-19 Mortality and Hospitalization, in Gastroenterology, 160(7), 2599-2601.e2.
A genetic variant in toll‐like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis
Nischalke Hans Dieter, Fischer Janett, Klüners Alexandra, Matz‐Soja Madlen, Krämer Benjamin, Langhans Bettina, Goeser Felix, Soyka Michael, Stickel Felix, Spengler Ulrich, Nattermann Jacob, Strassburg Christian P., Berg Thomas, Lutz Philipp (2021), A genetic variant in toll‐like receptor 5 is linked to chemokine levels and hepatocellular carcinoma in steatohepatitis, in Liver International, liv.14980-liv.14980.
Loss of hepatic Mboat7 leads to liver fibrosis
Thangapandi Veera Raghavan, Knittelfelder Oskar, Brosch Mario, Patsenker Eleonora, Vvedenskaya Olga, Buch Stephan, Hinz Sebastian, Hendricks Alexander, Nati Marina, Herrmann Alexander, Rekhade Devavrat Ravindra, Berg Thomas, Matz-Soja Madlen, Huse Klaus, Klipp Edda, Pauling Josch K, Wodke Judith AH, Miranda Ackerman Jacobo, Bonin Malte von, Aigner Elmar, Datz Christian, von Schönfels Witigo, Nehring Sophie, Zeissig Sebastian, et al. (2021), Loss of hepatic Mboat7 leads to liver fibrosis, in Gut, 70(5), 940-950.
Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis
BuchStephan (2021), Variants in PCSK7, PNPLA3 and TM6SF2 are risk factors for the development of cirrhosis in hereditary haemochromatosis, in Alimentary Pharmacology and Therapeutics, 53(7), 830-843.
rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis
Teo Kevin, Abeysekera Kushala W.M., Adams Leon, Aigner Elmar, Anstee Quentin M., Banales Jesus M., Banerjee Rajarshi, Basu Priyadarshi, Berg Thomas, Bhatnagar Pallav, Buch Stephan, Canbay Ali, Caprio Sonia, Chatterjee Ankita, Ida Chen Yii-Der, Chowdhury Abhijit, Daly Ann K., Datz Christian, de Gracia Hahn Dana, DiStefano Johanna K., Dong Jiawen, Duret Amedine, Emdin Connor, Fairey Madison, et al. (2021), rs641738C>T near MBOAT7 is associated with liver fat, ALT and fibrosis in NAFLD: A meta-analysis, in Journal of Hepatology, 74(1), 20-30.
Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1
Innes Hamish, Buch Stephan, Hutchinson Sharon, Guha Indra Neil, Morling Joanne R., Barnes Eleanor, Irving Will, Forrest Ewan, Pedergnana Vincent, Goldberg David, Aspinall Esther, Barclay Stephan, Hayes Peter C., Dillon John, Nischalke Hans Dieter, Lutz Philipp, Spengler Ulrich, Fischer Janett, Berg Thomas, Brosch Mario, Eyer Florian, Datz Christian, Mueller Sebastian, Peccerella Teresa, et al. (2020), Genome-Wide Association Study for Alcohol-Related Cirrhosis Identifies Risk Loci in MARC1 and HNRNPUL1, in Gastroenterology, 159(4), 1276-1289.e7.
Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers
Schneider Carolin V., Hamesch Karim, Gross Annika, Mandorfer Mattias, Moeller Linda S., Pereira Vitor, Pons Monica, Kuca Pawel, Reichert Matthias C., Benini Federica, Burbaum Barbara, Voss Jessica, Gutberlet Marla, Woditsch Vivien, Lindhauer Cecilia, Fromme Malin, Kümpers Julia, Bewersdorf Lisa, Schaefer Benedikt, Eslam Mohammed, Bals Robert, Janciauskiene Sabina, Carvão Joana, Neureiter Daniel, et al. (2020), Liver Phenotypes of European Adults Heterozygous or Homozygous for Pi∗Z Variant of AAT (Pi∗MZ vs Pi∗ZZ genotype) and Noncarriers, in Gastroenterology, 159(2), 534-548.e11.
Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers
Stickel Felix, Lutz Philipp, Buch Stephan, Nischalke Hans Dieter, Silva Ines, Rausch Vanessa, Fischer Janett, Weiss Karl Heinz, Gotthardt Daniel, Rosendahl Jonas, Marot Astrid, Elamly Mona, Krawczyk Marcin, Casper Markus, Lammert Frank, Buckley Thomas W. M., McQuillin Andrew, Spengler Ulrich, Eyer Florian, Vogel Arndt, Marhenke Silke, Felden Johann, Wege Henning, Sharma Rohini, et al. (2020), Genetic Variation in HSD17B13 Reduces the Risk of Developing Cirrhosis and Hepatocellular Carcinoma in Alcohol Misusers, in Hepatology, 72(1), 88-102.
The PNPLA3 I148M variant promotes lipid-induced hepatocyte secretion of CXC chemokines establishing a tumorigenic milieu
Nischalke Hans Dieter, Lutz Philipp, Bartok Eva, Krämer Benjamin, Langhans Bettina, Frizler Regina, Berg Thomas, Hampe Jochen, Buch Stephan, Datz Christian, Stickel Felix, Hartmann Gunther, Strassburg Christian P., Nattermann Jacob, Spengler Ulrich (2019), The PNPLA3 I148M variant promotes lipid-induced hepatocyte secretion of CXC chemokines establishing a tumorigenic milieu, in Journal of Molecular Medicine, 97(11), 1589-1600.
Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis
Stickel Felix, Buch Stephan, Nischalke Hans Dieter, Weiss Karl Heinz, Gotthardt Daniel, Fischer Janett, Rosendahl Jonas, Marot Astrid, Elamly Mona, Casper Markus, Lammert Frank, McQuillin Andrew, Zopf Steffen, Spengler Ulrich, Marhenke Silke, Kirstein Martha M., Vogel Arndt, Eyer Florian, von Felden Johann, Wege Henning, Buch Thorsten, Schafmayer Clemens, Braun Felix, Deltenre Pierre, et al. (2018), Genetic variants in PNPLA3 and TM6SF2 predispose to the development of hepatocellular carcinoma in individuals with alcohol-related cirrhosis, in American Journal of Gastroenterology, 113(10), 1475-1483.
Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis
Rosendahl Jonas, Kirsten Holger, Hegyi Eszter, Kovacs Peter, Weiss Frank Ulrich, Laumen Helmut, Lichtner Peter, Ruffert Claudia, Chen Jian-Min, Masson Emmanuelle, Beer Sebastian, Zimmer Constantin, Seltsam Katharina, Algül Hana, Bühler Florence, Bruno Marco J, Bugert Peter, Burkhardt Ralph, Cavestro Giulia Martina, Cichoz-Lach Halina, Farré Antoni, Frank Josef, Gambaro Giovanni, Gimpfl Sebastian, et al. (2018), Genome-wide association study identifies inversion in the CTRB1-CTRB2 locus to modify risk for alcoholic and non-alcoholic chronic pancreatitis, in Gut, 67(10), 1855-1863.
Genetic Contribution to Alcohol Dependence: Investigation of a Heterogeneous German Sample of Individuals with Alcohol Dependence, Chronic Alcoholic Pancreatitis, and Alcohol-Related Cirrhosis
Treutlein Jens, Frank Josef, Streit Fabian, Reinbold Céline, Juraeva Dilafruz, Degenhardt Franziska, Rietschel Liz, Witt Stephanie, Forstner Andreas, Ridinger Monika, Strohmaier Jana, Wodarz Norbert, Dukal Helene, Foo Jerome, Hoffmann Per, Herms Stefan, Heilmann-Heimbach Stefanie, Soyka Michael, Maier Wolfgang, Gaebel Wolfgang, Dahmen Norbert, Scherbaum Norbert, Müller-Myhsok Bertram, Lucae Susanne, et al. (2017), Genetic Contribution to Alcohol Dependence: Investigation of a Heterogeneous German Sample of Individuals with Alcohol Dependence, Chronic Alcoholic Pancreatitis, and Alcohol-Related Cirrhosis, in Genes, 8(7), 183-183.
The genetics of alcohol dependence and alcohol-related liver disease
Stickel Felix, Moreno Christophe, Hampe Jochen, Morgan Marsha Y. (2017), The genetics of alcohol dependence and alcohol-related liver disease, in Journal of Hepatology, 66(1), 195-211.

Collaboration

Group / person Country
Types of collaboration
Professor Dr. Dr. Andreas Teufel, Universitätsklinikum Regensburg Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Professor Dr. Jochen Hampe, Universitätsklinikum Carl-Gustav Carus der Universität Dresden Germany (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure
Professor Achim Weber, Institut für Klinische Pathologie, Universitätsspital Zürich Switzerland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
- Research Infrastructure

Associated projects

Number Title Start Funding scheme
138747 Genetic risk for alcoholic liver disease: in vivo analysis of susceptibility genes 01.12.2011 Project funding
138747 Genetic risk for alcoholic liver disease: in vivo analysis of susceptibility genes 01.12.2011 Project funding

Abstract

Hepatocellular carcinoma (HCC) is a serious complication of alcoholic liver cirrhosis (ALC) and shows a rising incidence worldwide. The premier premalignant risk factor for HCC in Western countries is cirrhosis, with a 10% incidence of HCC in alcoholic cirrhotics within 5 years of follow-up. To date, carriage of the PNPLA3 rs738409 (I148M) allele is the only robustly confirmed genetic risk locus predisposing to HCC, which however explains only a fraction of the host genetic risk in ALC.The present project pursues three major aims: 1. to identify genetic variants which reveal a significant association with HCC in patients with ALC by means of a genome-wide association study; 2. to elucidate the role and contribution of PNPLA3 I148M to the pathogenesis of HCC by using an ALC-HCC model in PNPLA3 I148M transgenic mice and stably transfected cell lines. 3. To study 1-(2) hitherto unknown risk variants as identified in aim 1, using the approaches established and described in aim 2.We will perform a GWAS comparing ALC with HCC (cases) vs ALC without HCC (controls) in European Caucasians, followed by validation of top hits in an independent European cohort. The GWAS and validation study will be executed using the HumanOmniExpress DNA BeadChip technology by Illumina, and TaqMan- and Sequenom-based replication genotyping of top hits, respectively. In vivo, C3H/He mice expressing the PNPLA3 I148M risk variant will be generated and used in an experimental model with chemically-induced HCC, with and without concomitant alcohol administration. Cell culture experiments with stably transfected Huh7 cell lines are scheduled to assay viability, migration, adhesion, invasion, and mRNA/protein expression. Newly identified risk variants derived from the GWAS will be analyzed using the same scheme.The proposed study has the potential to identify yet unknown genetic factors that determine the risk of ALC to develop HCC and to reveal the functional role of newly discovered risk genes in the pathogenesis of HCC. Identification and functional studies of such genetic risk factors would greatly improve our understanding of the host-environment interaction leading to HCC evolution, and hopefully will guide the development of preventive and therapeutic strategies.
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