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

• Published in: Journal of hepatology Vol. 58; no. 2; pp. 350 - 357
• Main Authors: Calderaro, Julien, Labrune, Philippe, Morcrette, Guillaume, Rebouissou, Sandra, Franco, Dominique, Prévot, Sophie, Quaglia, Alberto, Bedossa, Pierre, Libbrecht, Louis, Terracciano, Luigi, Smit, G. Peter A, Bioulac-Sage, Paulette, Zucman-Rossi, Jessica
• Format: Journal Article
• Language: English
• Published: Kidlington Elsevier B.V 01.02.2013; Elsevier
• Subjects: Adenoma, Liver Cell - epidemiology; Adenoma, Liver Cell - genetics; Adenoma, Liver Cell - metabolism; Adolescent; Adult; beta Catenin - genetics; beta Catenin - metabolism; Biological and medical sciences; Carbohydrates (enzymatic deficiencies). Glycogenosis; Carcinogenesis; Chromogranins; Comorbidity; Cytokine Receptor gp130 - genetics; Cytokine Receptor gp130 - metabolism; Errors of metabolism; Fatty acid synthesis; Female; Gastroenterology and Hepatology; Gastroenterology. Liver. Pancreas. Abdomen; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Glycogen storage disease; Glycogen Storage Disease Type I - epidemiology; Glycogen Storage Disease Type I - genetics; Glycogen Storage Disease Type I - metabolism; Glycolysis; GTP-Binding Protein alpha Subunits, Gs - genetics; GTP-Binding Protein alpha Subunits, Gs - metabolism; Hepatocellular adenoma; Hepatocellular carcinoma; 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; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Male; Medical sciences; Metabolic diseases; Metabolism; STAT3 Transcription Factor - genetics; STAT3 Transcription Factor - metabolism; Tumors; Young Adult; inflammatory adenoma; HCA; bHCA; CTNNB1 mutated adenoma; HCC; unclassified adenoma; Glycogen storage disease; Metabolism; H-HCA; Carcinogenesis; hepatocellular adenoma; HNF1A-inactivated adenoma; UHCA; glycogen storage disease type I; Glycolysis; GSD; hepatocellular carcinoma; IHCA; Fatty acid synthesis; Hepatocellular adenoma; Hepatocellular carcinoma; Human; Metabolic diseases; Hepatic disease; Malignant tumor; Adenoma; Enzymopathy; Fatty acids; Genetic disease; Synthesis; Glycogenosis I Von Gierke; Gastroenterology; Digestive diseases; Carbohydrate; Benign neoplasm; Cancer
• ISSN: 0168-8278; 1600-0641
• DOI: 10.1016/j.jhep.2012.09.030

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.