Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I

J Hepatol. 2013 Feb;58(2):350-7. doi: 10.1016/j.jhep.2012.09.030. Epub 2012 Oct 6.


Background & aims: Hepatocellular adenomas (HCA) are benign liver tumors mainly related to oral contraception and classified into 4 molecular subgroups: inflammatory (IHCA), HNF1A-inactivated (H-HCA), β-catenin-activated (bHCA) or unclassified (UHCA). Glycogen storage disease type I (GSD) is a rare hereditary metabolic disease that predisposes to HCA development. The aim of our study was to characterize the molecular profile of GSD-associated HCA.

Methods: We characterized a series of 25 HCAs developed in 15 patients with GSD by gene expression and DNA sequence of HNF1A, CTNNB1, IL6ST, GNAS, and STAT3 genes. Moreover, we searched for glycolysis, gluconeogenesis, and fatty acid synthesis alterations in GSD non-tumor livers and compared our results to those observed in a series of sporadic H-HCA and various non-GSD liver samples.

Results: GSD adenomas were classified as IHCA (52%) mutated for IL6ST or GNAS, bHCA (28%) or UHCA (20%). In contrast, no HNF1A inactivation was observed, showing a different molecular subtype distribution in GSD-associated HCA from that observed in sporadic HCA (p = 0.0008). In non-tumor GSD liver samples, we identified glycolysis and fatty acid synthesis activation with gluconeogenesis repression. Interestingly, this gene expression profile was similar to that observed in sporadic H-HCA.

Conclusions: Our study showed a particular molecular profile in GSD-related HCA characterized by a lack of HNF1A inactivation. This exclusion could be explained by similar metabolic defects observed with HNF1A inactivation and glucose-6-phosphatase deficiency. Inversely, the high frequency of β-catenin mutations could be related to the increased frequency of malignant transformation in hepatocellular carcinoma.

Publication types

  • Comparative Study
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenoma, Liver Cell / epidemiology*
  • Adenoma, Liver Cell / genetics*
  • Adenoma, Liver Cell / metabolism
  • Adolescent
  • Adult
  • Chromogranins
  • Comorbidity
  • Cytokine Receptor gp130 / genetics
  • Cytokine Receptor gp130 / metabolism
  • Female
  • GTP-Binding Protein alpha Subunits, Gs / genetics
  • GTP-Binding Protein alpha Subunits, Gs / metabolism
  • Gene Expression Profiling*
  • Gene Expression Regulation, Neoplastic
  • Glycogen Storage Disease Type I / epidemiology*
  • Glycogen Storage Disease Type I / genetics*
  • Glycogen Storage Disease Type I / metabolism
  • Hepatocyte Nuclear Factor 1-alpha / genetics
  • Hepatocyte Nuclear Factor 1-alpha / metabolism
  • Humans
  • Liver / metabolism
  • Liver / pathology
  • Liver Neoplasms / epidemiology*
  • Liver Neoplasms / genetics*
  • Liver Neoplasms / metabolism
  • Male
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Young Adult
  • beta Catenin / genetics
  • beta Catenin / metabolism


  • CTNNB1 protein, human
  • Chromogranins
  • HNF1A protein, human
  • Hepatocyte Nuclear Factor 1-alpha
  • IL6ST protein, human
  • STAT3 Transcription Factor
  • STAT3 protein, human
  • beta Catenin
  • Cytokine Receptor gp130
  • GNAS protein, human
  • GTP-Binding Protein alpha Subunits, Gs