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Background:  Potential prognostic biomarker candidates for hepatocellular carcinoma (HCC) are abundant, but their generalizability is unexplored. We cross-validated markers of overall survival (OS) and vascular invasion in independent datasets.  Methods:  The literature search yielded 318 genes related to survival and 52 related to vascular invasion. Validation was performed in three datasets (RNA-seq,  n  = 371; Affymetrix arrays,  n  = 91; Illumina gene chips,  n  = 135) by uni- and multivariate Cox regression and Mann–Whitney  U -test, separately for Asian and Caucasian patients.  Results:  One hundred and eighty biomarkers remained significant in Asian and 128 in Caucasian subjects at  p  < 0.05. After multiple testing correction  BIRC5  ( p  = 1.9 × 10 −10 ),  CDC20  ( p  = 2.5 × 10 −9 ) and  PLK1  ( p  = 3 × 10 −9 ) endured as best performing genes in Asian patients; however, none remained significant in the Caucasian cohort. In a multivariate analysis, significance was reached by stage ( p  = 0.0018) and expression of  CENPH  ( p  = 0.0038) and  CDK4  ( p  = 0.038).  KIF18A  was the only gene predicting vascular invasion in the Affymetrix and Illumina cohorts ( p  = 0.003 and  p  = 0.025, respectively).  Conclusion:  Overall, about half of biomarker candidates failed to retain prognostic value and none were better than stage predicting OS. Impact: Our results help to eliminate biomarkers with limited capability to predict OS and/or vascular invasion.

Determining consistent prognostic biomarkers of overall survival and vascular invasion in hepatocellular carcinoma