Abstract
Early diagnosis of hepatocellular carcinoma (HCC) remains challenging to date. Characteristic metabolic deregulations of HCC may enable novel biomarkers discovery for early diagnosis. A capillary electrophoresis-time of flight mass spectrometry (CE-TOF/MS)-based metabolomics approach was performed to discover and validate potential biomarkers for HCC from the diethylnitrosamine-induced rat hepatocarcinogenesis model to human subjects. Time series sera from the animal model were evaluated using multivariate and univariate analyses to reveal dynamic metabolic changes. Two independent human cohorts (populations I and II) containing 122 human serum specimens were enrolled for validations. A novel biomarker pattern of ratio creatine/betaine which reflects the balance of methylation was identified. This biomarker pattern achieved effective classification of pre-HCC and HCC stages in animal model. It was still effective in the diagnosis of HCC from high-risk patients with cirrhotic nodules, achieving AUC values of 0.865 and 0.905 for two validation cohorts, respectively. The diagnosis of small HCC from cirrhosis with an AUC of 0.928 highlighted the potential for early diagnosis. This ratio biomarker can also improve the diagnostic performance of α-fetoprotein (AFP). This study demonstrates the efficacy of present strategy for biomarker discovery, and the potential of metabolomics approach to provide novel insights for disease study.
Highlights
Hepatocellular carcinoma (HCC) is the most common liver neoplasm with high lethality (< 7% of a five-year survival rate)[1]
Histological sections verified that the DEN-induced hepatocarcinogenesis model was successfully produced in this study
Considering the fact that it is difficult to collect samples from hepatocellular carcinoma (HCC) patients at a very early stage due to the fast development of tumorigenesis and challenging early discovery, the DEN animal model was employed to imitate the process of stepwise hepatocarcinogenesis
Summary
Hepatocellular carcinoma (HCC) is the most common liver neoplasm with high lethality (< 7% of a five-year survival rate)[1]. A series of studies about individual metabolites or their combination, such as serum γ -glutamyl dipeptides[13], bile acids[2], fatty acids[14], sphingosines[15] and urine carnitine[16], have been reported to distinguish different forms of hepatic disease These studies enrich the pool of potential biomarkers for future clinical application. Time series samples would be necessary for such dynamic metabolomics study, which would be possible to provide insight into the interfacial stage between precancerous cirrhosis and HCC, and further facilitate the screening of biomarkers for early diagnosis. Our findings indicated that the metabolic deregulations in rat models are similar to patients, and it would be possible to discover potential biomarkers for early diagnosis. Since polar and ionic metabolites are well recognized for tumorigenesis, suppression and signaling[10,11,21,22], more such metabolites should be concerned in subsequent studies
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