Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease

Salvatore Petta, Alessio Aghemo, Chao Xing, Benedetta Donati, Alessandro Pietrelli, Serena Pelusi, Antonio Grieco, Marica Meroni, Guido Baselli, Misti Vanette Mccain, Giorgio Soardo, Roberta D’Ambrosio, Stefano Romeo, Raffaele De Francesco, Paola Dongiovanni, Elisabetta Bugianesi, Anna Ludovica Fracanzani, Luca Vittorio Carlo Valenti, Helen Louise Reeves, Luca MieleSilvia Fargion, Renato Romagnoli

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Abstract

Nonalcoholic fatty liver disease (NAFLD) is a rising cause of hepatocellular carcinoma (HCC). We examined whether inherited pathogenic variants in candidate genes (n = 181) were enriched in patients with NAFLD-HCC. To this end, we resequenced peripheral blood DNA of 142 NAFLD-HCC, 59 NAFLD with advanced fibrosis, and 50 controls, and considered 404 healthy individuals from 1000 G. Pathogenic variants were defined according to ClinVar, likely pathogenic as rare variants predicted to alter protein activity. In NAFLD-HCC patients, we detected an enrichment in pathogenic (p = 0.024), and likely pathogenic variants (p = 1.9*10-6), particularly in APOB (p = 0.047). APOB variants were associated with lower circulating triglycerides and higher HDL cholesterol (p < 0.01). A genetic risk score predicted NAFLD-HCC (OR 4.96, 3.29-7.55; p = 5.1*10-16), outperforming the diagnostic accuracy of common genetic risk variants, and of clinical risk factors (p < 0.05). In conclusion, rare pathogenic variants in genes involved in liver disease and cancer predisposition are associated with NAFLD-HCC development.
Lingua originaleEnglish
pagine (da-a)3682-
Numero di pagine10
RivistaScientific Reports
Volume9
Stato di pubblicazionePublished - 2019

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Petta, S., Aghemo, A., Xing, C., Donati, B., Pietrelli, A., Pelusi, S., Grieco, A., Meroni, M., Baselli, G., Mccain, M. V., Soardo, G., D’Ambrosio, R., Romeo, S., De Francesco, R., Dongiovanni, P., Bugianesi, E., Fracanzani, A. L., Valenti, L. V. C., Reeves, H. L., ... Romagnoli, R. (2019). Rare Pathogenic Variants Predispose to Hepatocellular Carcinoma in Nonalcoholic Fatty Liver Disease. Scientific Reports, 9, 3682-.