Specificities of Hepatocellular Carcinoma Developed on Non Alcoholic Fatty Liver Disease in Absence of Cirrhosis Revealed by Tissue 1H-NMR Spectroscopy

SESSION 6 - CANCER-RELATED MALNUTRITION, METABOLISM, DYSIMMUNITYSESSION 6 - CANCER-RELATED MALNUTRITION, METABOLISM, DYSIMMUNITYBackground and aims:Epidemiologic studies suggest that NAFLD increases the risk of Hepato-Cellular Carcinoma (HCC),even in non-cirrhotic NAFLD. This underlying disease is reported in up to 40% HCC.To get insights into the biology of HCC in non-cirrhotic NAFLD and seek for putative cancer pathways, we performed metabolomics in HCC associated with cirrhosis and non-cirrhotic NAFLD.Methods:Metabolomics was performed using 1H-NMR Spectroscopy. The analysis included 28 pairs of HCC tissue and distant Non-Involved Tissue (NIT) collected from patients undergoing hepatectomy. HCC was associated with cirrhosis (n = 9), normal liver (n=6) or NAFLD (n = 13).Results:In HCC versus NIT, statistical analyses showed high level of lactate and phosphocholine and low level of glucose. Multivariate analysis of HCC groups showed increased level of β-hydroxybutyrate in HCC-Cirrhosis and increased level of glutamine in HCC-NAFLD. OPLS-DA models of HCC-cirrhosis vs NIT (either normal tissue or cirrhosis) and HCC-NAFLD vs NIT (either normal tissue or NAFLD) were constructed before comparing them in shared and unique structure (SUS) plots. From SUS-plots, HCC-Cirrhosis was characterized by high levels of β-hydroxybutyrate, tyrosine and phenylalanine, whereas HCC-NAFLD was characterized by high levels of glutamine/glutamate. Glutamine Synthetase (GS) immuno-staining was correlated with the NMR-spectroscopy glutamine quantification.Conclusion:This study provides evidence of metabolic specificities of HCC associated with non-cirrhotic NAFLD versus HCC associated with cirrhosis. These alterations could suggest activation of glutamine synthetase pathway in HCC-NAFLD and mitochondrial dysfunction in HCC-cirrhosis, that may be part of specific carcinogenic processe