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

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

Research output: Contribution to journalArticlepeer-review

73 Scopus citations


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.

Original languageEnglish (US)
Article number3682
JournalScientific reports
Issue number1
StatePublished - Dec 1 2019

ASJC Scopus subject areas

  • General


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