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Non-invasive stratification of hepatocellular carcinoma risk in non-alcoholic fatty liver using polygenic risk scores.

Translational Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Department of Clinical and Molecular Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden. Translational Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Clinic of Internal Medicine - Liver Unit, Department of Medical Area (DAME), Università degli Studi di Udine, Udine, Italy. Department of Internal Medicine, Fondazione Policlinico A. Gemelli, Università Cattolica di Roma, Rome, Italy. Unit of Medicine, ASST Valle Olona, Ospedale di Gallarate, Varese, Italy. Division of Gastroenterology and Hepatology, CRC "A.M. and A. Migliavacca" Center for Liver Disease, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Research Unit of Molecular Genetics of Complex Phenotypes, IRCCS Ospedale Bambino Gesù, Rome, Italy. Division of Hepatogastroenterology, Deparment of Precision Medicine, Università della Campania "Luigi Vanvitelli", Naples, Italy. Department of Medical Sciences, Division of Gastro-Hepatology, A.O. Città della Salute e della Scienza di Torino, Università di Torino, Turin, Italy. Gastroenterology and Hepatology, PROMISE, Università di Palermo, Palermo, Italy. Department of Hepatology, University Campus Bio-Medico di Roma, Rome, Italy. Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne, UK; Newcastle NIHR Biomedical Research Centre, Newcastle upon Tyne Hospitals NHS Foundation Trust, Newcastle upon Tyne, UK. Department of Gastroenterology and Hepatology, University Hospital of Zürich, Switzerland. Medical Department 1, University Hospital Dresden, TU Dresden, Germany. Division of Hepatology, Department of Medicine II, Leipzig University Medical Center, Laboratory for Clinical and Experimental Hepatology, Leipzig, Germany. Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy; General Medicine and Metabolic Diseases, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy. Clinic of Internal Medicine - Liver Unit, Department of Medical Area (DAME), Università degli Studi di Udine, Udine, Italy; Italian Liver Foundation, Area Science Park, Basovizza Campus, Trieste, Italy. Department of Clinical and Molecular Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden; Clinical Nutrition Unit, Department of Medical and Surgical Science, University Magna Graecia, Catanzaro, Italy. Electronic address: stefano.romeo@wlab.gu.se. Translational Medicine - Department of Transfusion Medicine and Hematology, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, Milan, Italy; Department of Pathophysiology and Transplantation, Università degli Studi di Milano, Milan, Italy. Electronic address: luca.valenti@unimi.it.

Journal of hepatology. 2021;(4):775-782
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Abstract

BACKGROUND & AIMS Hepatocellular carcinoma (HCC) risk stratification in individuals with dysmetabolism is a major unmet need. Genetic predisposition contributes to non-alcoholic fatty liver disease (NAFLD). We aimed to exploit robust polygenic risk scores (PRS) that can be evaluated in the clinic to gain insight into the causal relationship between NAFLD and HCC, and to improve HCC risk stratification. METHODS We examined at-risk individuals (NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD) and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC). Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS (PRS-HFC), and then adjusted for HSD17B13 (PRS-5). RESULTS In the NAFLD cohort, the adjusted impact of genetic risk variants on HCC was proportional to the predisposition to fatty liver (p = 0.002) with some heterogeneity in the effect. PRS predicted HCC more robustly than single variants (p <10-13). The association between PRS and HCC was mainly mediated through severe fibrosis, but was independent of fibrosis in clinically relevant subgroups, and was also observed in those without severe fibrosis (p <0.05). In the UKBB cohort, PRS predicted HCC independently of classical risk factors and cirrhosis (p <10-7). In the NAFLD cohort, we identified high PRS cut-offs (≥0.532/0.495 for PRS-HFC/PRS-5) that in the UKBB cohort detected HCC with ~90% specificity but limited sensitivity; PRS predicted HCC both in individuals with (p <10-5) and without cirrhosis (p <0.05). CONCLUSIONS Our results are consistent with a causal relationship between hepatic fat and HCC. PRS improved the accuracy of HCC detection and may help stratify HCC risk in individuals with dysmetabolism, including those without severe liver fibrosis. Further studies are needed to validate our findings. LAY SUMMARY By analyzing variations in genes that contribute to fatty liver disease, we developed two risk scores to help predict liver cancer in individuals with obesity-related metabolic complications. These risk scores can be easily tested in the clinic. We showed that the risk scores helped to identify the risk of liver cancer both in high-risk individuals and in the general population.