title: Molecular characterization of hepatocellular adenomas developed in patients with glycogen storage disease type I.
abstract: OBJECTIVE
  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.
authors.affiliation: Inserm, UMR-674, Génomique fonctionnelle des tumeurs solides, IUH, F-75010 Paris, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Calderaro
authors.forename: Philippe
authors.initials: P
authors.lastname: Labrune
authors.forename: Guillaume
authors.initials: G
authors.lastname: Morcrette
authors.forename: Sandra
authors.initials: S
authors.lastname: Rebouissou
authors.forename: Dominique
authors.initials: D
authors.lastname: Franco
authors.forename: Sophie
authors.initials: S
authors.lastname: Prévot
authors.forename: Alberto
authors.initials: A
authors.lastname: Quaglia
authors.forename: Pierre
authors.initials: P
authors.lastname: Bedossa
authors.forename: Louis
authors.initials: L
authors.lastname: Libbrecht
authors.forename: Luigi
authors.initials: L
authors.lastname: Terracciano
authors.forename: G Peter A
authors.initials: GP
authors.lastname: Smit
authors.forename: Paulette
authors.initials: P
authors.lastname: Bioulac-Sage
authors.forename: Jessica
authors.initials: J
authors.lastname: Zucman-Rossi
mesh_terms: D018248:Adenoma, Liver Cell / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D000293:Adolescent; D000328:Adult; D002864:Chromogranins; D015897:Comorbidity; D050822:Cytokine Receptor gp130 / Q000235:genetics / Q000378:metabolism; D005260:Female; D019205:GTP-Binding Protein alpha Subunits, Gs / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D005953:Glycogen Storage Disease Type I / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology; D008113:Liver Neoplasms / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D008297:Male; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D055815:Young Adult; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: C495270:CTNNB1 protein, human; D002864:Chromogranins; C496487:HNF1A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; C494199:IL6ST protein, human; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D051176:beta Catenin; D050822:Cytokine Receptor gp130; C406732:GNAS protein, human; D019205:GTP-Binding Protein alpha Subunits, Gs