title: Metabolomics Identifies Biomarker Pattern for Early Diagnosis of Hepatocellular Carcinoma: from Diethylnitrosamine Treated Rats to Patients.
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.
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Jun
authors.initials: J
authors.lastname: Zeng
authors.affiliation: School of Computer Science &Technology, Dalian University of Technology, 116024 Dalian, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Lina
authors.initials: L
authors.lastname: Zhou
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China.
authors.forename: Yexiong
authors.initials: Y
authors.lastname: Tan
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Chunxiu
authors.initials: C
authors.lastname: Hu
authors.affiliation: Department of Hepatology, First Hospital, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Xiaomei
authors.initials: X
authors.lastname: Wang
authors.affiliation: Department of Hepatology, First Hospital, Jilin University, Changchun, Jilin 130021, China.
authors.forename: Junqi
authors.initials: J
authors.lastname: Niu
authors.affiliation: International Cooperation Laboratory on Signal Transduction, Eastern Hepatobiliary Surgery Institute, the Second Military Medical University, Shanghai, China.
authors.forename: Hongyang
authors.initials: H
authors.lastname: Wang
authors.affiliation: School of Computer Science &Technology, Dalian University of Technology, 116024 Dalian, China.
authors.forename: Xiaohui
authors.initials: X
authors.lastname: Lin
authors.affiliation: Key Laboratory of Separation Science for Analytical Chemistry, Dalian Institute of Chemical Physics, Chinese Academy of Sciences, Dalian 116023, China.
authors.forename: Peiyuan
authors.initials: P
authors.lastname: Yin
mesh_terms: D000818:Animals; D001622:Betaine / Q000097:blood; D014408:Biomarkers, Tumor / Q000097:blood*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000175:diagnosis* / Q000473:pathology; D015331:Cohort Studies; D003401:Creatine / Q000097:blood; D004052:Diethylnitrosamine / Q000633:toxicity; D004195:Disease Models, Animal; D042241:Early Diagnosis; D005260:Female; D006801:Humans; D008113:Liver Neoplasms / Q000139:chemically induced / Q000175:diagnosis* / Q000473:pathology; D008297:Male; D055432:Metabolomics; D015999:Multivariate Analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D000509:alpha-Fetoproteins / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; D000509:alpha-Fetoproteins; D004052:Diethylnitrosamine; D001622:Betaine; D003401:Creatine