Metabolomic profiles of hepatocellular carcinoma in a European prospective cohort

Abstract

BackgroundHepatocellular carcinoma (HCC), the most prevalent form of liver cancer, is difficult to diagnose and has limited treatment options with a low survival rate. Aside from a few key risk factors, such as hepatitis, high alcohol consumption, smoking, obesity, and diabetes, there is incomplete etiologic understanding of the disease and little progress in identification of early risk biomarkers.MethodsTo address these aspects, an untargeted nuclear magnetic resonance metabolomic approach was applied to pre-diagnostic serum samples obtained from first incident, primary HCC cases (n = 114) and matched controls (n = 222) identified from amongst the participants of a large European prospective cohort.ResultsA metabolic pattern associated with HCC risk comprised of perturbations in fatty acid oxidation and amino acid, lipid, and carbohydrate metabolism was observed. Sixteen metabolites of either endogenous or exogenous origin were found to be significantly associated with HCC risk. The influence of hepatitis infection and potential liver damage was assessed, and further analyses were made to distinguish patterns of early or later diagnosis.ConclusionOur results show clear metabolic alterations from early stages of HCC development with application for better etiologic understanding, prevention, and early detection of this increasingly common cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12916-015-0462-9) contains supplementary material, which is available to authorized users.

A Systematic Evaluation of Blood Serum and Plasma Pre-Analytics for Metabolomics Cohort Studies

“…The parallel development of biobanking and high-throughput sequencing, genotyping and phenotyping technologies has enabled a new generation of successful molecular epidemiology studies, such as genome-wide association studies (GWAS) [1], metabolome-wide association studies (MWAS) [2,3] and even metabolomics GWASes [4,5,6]. It currently provides a wide range of new opportunities for the development of biomarkers of medical interest with current applications in toxicology [7], cancer [8,9,10], cardiovascular disease [11,12], prediction of treatment outcomes [13,14,15] or “pharmacometabonomics” [16,17], and more recently metabolic modelling of the patient journey in a clinical environment [18,19].…”

Lipid Metabolism in Liver Cancer

“…Another Chinese study, which used tryptophan, glutamine, and 2-hydroxybutyric acid as biomarkers in 183 human serum, also achieved high accuracy (AUC: 0.969-0.990) in both training and validation dataset [69]. Furthermore, the aforementioned European study [80] also demonstrated better diagnostic performance of metabolites than alpha-fetoprotein and liver enzymes.…”

“…A recent nested case-control study from a large European prospective cohort compared serums collected before diagnosis in 114 HCC with 222 matched controls and carefully controlled possible confounders such as tobacco usage, alcohol consumption, and so on [80]. Sixteen metabolites involved in amino acid metabolism, choline metabolism, polyunsaturated lipid metabolism, and ammonium detoxication were selected for potential biomarkers.…”

Plasma metabolomic analysis of human hepatocellular carcinoma: Diagnostic and therapeutic study

“…Fages et al . found sixteen metabolites in serum were significantly associated with HCC risk of a European prospective cohort [17]. Other studies show significant differences between compensated and decompensated cirrhosis, and between alcoholic cirrhosis and viral hepatitis [18–20].…”

“…The influence of hepatitis infection and potential liver damage were simultaneously assessed [21, 22]. To date, several NMR or mass spectrometry-based serum metabolomic studies have been conducted to study HCC [17, 19, 20, 23]. And discriminatory metabolic alterations in HCC patients could draw a basic conclusion that altered mitochondrial respiration and glycolytic pathways lead to altered metabolic profiles in tumor cells [24, 25], but the identified metabolites are not concordant across these studies.…”