title: The Prediction of Clinical Outcome in Hepatocellular Carcinoma Based on a Six-Gene Metastasis Signature.
abstract: OBJECTIVE
  The dismal outcome of hepatocellular carcinoma (HCC) is largely attributed to its early recurrence and venous metastases. We aimed to develop a metastasis-related model to predict hepatocellular carcinoma prognosis.
  
  
  METHODS
  Using microarrays, sequencing, and RT-PCR, we measured the expression of mRNAs and lncRNAs in a training set of 94 well-defined low-risk (LRM) and high-risk metastatic (HRM) HCC patients from a Shanghai cohort. We refined a metastasis signature and established a corresponding model using logistic regression analysis. The validation set consisted of 567 HCC patients from four-center cohorts. Survival analysis was performed according to the metastasis model.
  
  
  RESULTS
  Using relative expression of tumor to para-tumor tissues, we refined the metastasis signature of five mRNAs and one lncRNA. A generalized linear model was further established to predict the probability of metastasis (MP). Using MP cutoff of 0.7 to separate LRM and HRM in Shanghai cohort, the specificity and sensitivity of the model were 96% [95% confidence interval (CI), 85%-99%] and 74% (95% CI, 58%-86%), respectively. Furthermore, HRM patients showed a significantly shorter overall and recurrence-free survival in validation cohorts (P < 0.05 for each cohort). Early HCC patients also have a poorer outcome for multicenter HRM patients. Finally, Cox regression analysis indicated that continuous MP was an independent risk factor and associated with the recurrence and survival of HCC patients after resection (HR 2.98-16.6, P < 0.05).
  
  
  CONCLUSIONS
  We developed an applicable six-gene metastasis signature, which is robust and reproducible in multicenter cohorts for HCC prognosis. Clin Cancer Res; 23(1); 289-97. ©2016 AACR.
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Shengxian
authors.initials: S
authors.lastname: Yuan
authors.affiliation: The Wilmer Eye Institute, Johns Hopkins University School of Medicine, Baltimore, Maryland. ehphwp3@126.com msswjw@163.com li_lequn@263.net kclin2002@126.com liulei@scbit.org.
authors.forename: Jie
authors.initials: J
authors.lastname: Wang
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Yang
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Jin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Hui
authors.initials: H
authors.lastname: Liu
authors.affiliation: Key Laboratory of Systems Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, Shanghai, China.
authors.forename: Juanjuan
authors.initials: J
authors.lastname: Xiao
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China.
authors.forename: Qingguo
authors.initials: Q
authors.lastname: Xu
authors.affiliation: Mengchao Hepatobiliary Hospital of Fujian Medical University, Fujian, China.
authors.forename: Xinhui
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China.
authors.forename: Bangde
authors.initials: B
authors.lastname: Xiang
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China.
authors.forename: Shaoliang
authors.initials: S
authors.lastname: Zhu
authors.affiliation: Department of Hepatobiliary Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Guangxi, China. ehphwp3@126.com msswjw@163.com li_lequn@263.net kclin2002@126.com liulei@scbit.org.
authors.forename: Lequn
authors.initials: L
authors.lastname: Li
authors.affiliation: Mengchao Hepatobiliary Hospital of Fujian Medical University, Fujian, China. ehphwp3@126.com msswjw@163.com li_lequn@263.net kclin2002@126.com liulei@scbit.org.
authors.forename: Jingfeng
authors.initials: J
authors.lastname: Liu
authors.affiliation: Shanghai Public Health Clinical Center, and Institutes of Biomedical Sciences, Fudan University, Shanghai, China. ehphwp3@126.com msswjw@163.com li_lequn@263.net kclin2002@126.com liulei@scbit.org.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: The Third Department of Hepatic Surgery, Eastern Hepatobiliary Hospital, Second Military Medical University, Shanghai, China. ehphwp3@126.com msswjw@163.com li_lequn@263.net kclin2002@126.com liulei@scbit.org.
authors.forename: Weiping
authors.initials: W
authors.lastname: Zhou
mesh_terms: D000328:Adult; D014408:Biomarkers, Tumor; D006528:Carcinoma, Hepatocellular / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D008113:Liver Neoplasms / Q000175:diagnosis / Q000235:genetics* / Q000401:mortality*; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011379:Prognosis; D062085:RNA, Long Noncoding / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D012372:ROC Curve; D015203:Reproducibility of Results; D016019:Survival Analysis; D057188:Workflow
chemical_list: D014408:Biomarkers, Tumor; D062085:RNA, Long Noncoding; D012333:RNA, Messenger