Abstract 2344: Shotgun metabolomics revealed possible reprogrammed pathways that shift for cancer development in non-alcoholic steatohepatitis
Authors: Marwa O. El-Derany, Eman Ahmed, Ali M. Anwar, Sameh Magdeldin
Journal: Cancer Research (2021)

Abstract Purpose: The future prevalence of hepatocellular carcinoma (HCC) is expected to become further divergent with the emergence of non-alcoholic steatohepatitis (NASH) as a major contributor. Multiple etiologies are associated with the development of HCC each is characterized by specific pattern of metabolic dysregulations. The identification of the metabolic readouts that function in pathways reprograming for HCC development from NASH is still far from clear. Materials and Methods: Well diagnosed Sixty-one patients were recruited. They were divided into thirty-one NASH patients and thirty HCC patients developed from NASH (HCC-NASH) based on biochemical, hematological parameters and on serum levels of alpha-fetoprotein and other clinical characteristics, radiological and histological analysis. Fasting serum samples were screened for the metabolic profile of NASH and HCC-NASH patients using LC-MS/MS Triple TOF. Subsequently, multivariate data analysis, machine learning, receiver-operating curves and ingenuity pathway analysis were conducted to explore the metabolic signature that could robustly determine the causative metabolite which function for understanding, predicting and targeting HCC in NASH patients. Results: Our study showed a panel of thirty metabolites completely segregating HCC-NASH from NASH patients at folds change &amp;gt;2. Of these small molecules, some were positively associated with HCC in NASH patients including L-carnitine, 2-methylglutaric acid, adipic acid, serotonin, gamma- and alpha linolenic acid, L-alloisoleucine, L-arginine, N-methyl-L-glutamic Acid, pyroglutamic acid, (R)-salsolinol, L-histidine, progesterone, 1,9 and 1,3 -dimethyluric acid, citrulline, N-acetyl-L-methionine, D-malic acid, clupanodonic, cortisone and L-octanoylcarnitine. On the other side, daidzein, 5'-methylthioadenosine, L-lysine, niacinamide, L-aspartic acid, genistein, guanosine, 5- hydroxyeicosatetraenoic and naringin were negatively associated with the development of HCC in NASH patients. The area under the receiving operating curve showed that our pattern of metabolites has a predictive power of 90%. These metabolites function in specific pathways perpetuation most importantly related to the transport of bile salts and organic acids, metal ions and amine compounds, fatty acid metabolism, tricarboxylic acid cycle, neurotransmitter clearance, metabolism of serotonin and proline catabolism. Alternatively, gluconeogenesis, purine salvage, phenylalanine metabolism, and sirtuin 1 negatively regulates rRNA expression were significantly downregulated in HCC-NASH as compared to NASH patients. Conclusion: This study provided for the first time a specific pattern of metabolites with a detailed map for the most predominant perpetuated metabolic pathways that could understand, predict and target HCC development from NASH. Citation Format: Marwa O. El-Derany, Eman Ahmed, Ali M. Anwar, Sameh Magdeldin. Shotgun metabolomics revealed possible reprogrammed pathways that shift for cancer development in non-alcoholic steatohepatitis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2344.