Evaluation of Metabolite Biomarkers for Hepatocellular Carcinoma through Stratified Analysis by Gender, Race, and Alcoholic Cirrhosis

Abstract

Background The effects of hepatocellular carcinoma (HCC) on liver metabolism and circulating metabolites have been subjected to continuing investigation. This study compares the levels of selected metabolites in sera of HCC cases versus patients with liver cirrhosis and evaluates the influence of gender, race, and alcoholic cirrhosis on the performance of the metabolites as candidate biomarkers for HCC. Methods Targeted quantitation of 15 metabolites is performed by selected research monitoring (SRM) in sera from 89 Egyptian subjects (40 HCC cases and 49 cirrhotic controls) and 110 US subjects (56 HCC cases and 54 cirrhotic controls). Logistic regression models are used to evaluate the ability of these metabolites in distinguishing HCC cases from cirrhotic controls. The influences of gender, race, and alcoholic cirrhosis on the performance of the metabolites are analyzed by stratified logistic regression. Results Two metabolites are selected based on their significance to both cohorts. While both metabolites discriminate HCC cases from cirrhotic controls in males and Caucasians, they are insignificant in females and African Americans. One metabolite is significant in patients with alcoholic cirrhosis and the other in non-alcoholic cirrhosis. Conclusions The study demonstrates the potential of two metabolites as candidate biomarkers for HCC by combining them with α-fetoprotein and gender. Stratified statistical analyses reveal that gender, race, and alcoholic cirrhosis affect the relative levels of small molecules in serum. Impact The findings of this study contribute to a better understanding of the influence of gender, race, and alcoholic cirrhosis in investigating small molecules as biomarkers for HCC.

Sugar Alcohols Have a Key Role in Pathogenesis of Chronic Liver Disease and Hepatocellular Carcinoma in Whole Blood and Liver Tissues

“…As commonly observed [37][38][39], HCC cases were dominated by men, with only 26% of the cases presented by women (Table 2). Single focal lesions represented 65% of the cases, and lesions <5 cm in size represented 83% of the cases.…”

GC-MS Based Plasma Metabolomics for Identification of Candidate Biomarkers for Hepatocellular Carcinoma in Egyptian Cohort

“…Citric acid was also found to be significantly different between HCC cases and cirrhotic controls in serum [ 15 ]. We previously observed down-regulation of bile acids and up-regulation of phospholipids and amino acids in HCC cases vs. cirrhotic controls through metabolomics analysis of sera by LC-MS [ 16 – 18 ]. Specifically, we observed down-regulation of long chain carnitine, oleoyl carnitine, palmitoyl carnitine, and linoelaidyl carnitine in HCC patients compared with cirrhotic controls.…”

Heat Shock Protein 70 Serum Levels Differ Significantly in Patients with Chronic Hepatitis, Liver Cirrhosis, and Hepatocellular Carcinoma

“…Immunohistochemical analysis of tumor biopsies suggests that HSP70 in combination with other markers such as glutamine synthetase could serve as a putative diagnostic marker in HCC ( 6 ). Apart from HCC ( 13 ), an elevated expression of HSP70 was also found in patients with early-stage pancreatic cancer ( 14 ). High cytosolic HSP70 levels can promote tumor growth, prevent apoptotic cell death and thus are often associated resistance to therapy and poor prognosis in many different cancer types ( 8 ).…”