Molecular portrait of high alpha-fetoprotein in hepatocellular carcinoma: implications for biomarker-driven clinical trials

Br J Cancer. 2019 Aug;121(4):340-343. doi: 10.1038/s41416-019-0513-7. Epub 2019 Jul 9.


The clinical utility of serum alpha-fetoprotein (AFP) in patients with hepatocellular carcinoma (HCC) is widely recognised. However, a clear understanding of the mechanisms of AFP overexpression and the molecular traits of patients with AFP-high tumours are not known. We assessed transcriptome data, whole-exome sequencing data and DNA methylome profiling of 520 HCC patients from two independent cohorts to identify distinct molecular traits of patients with AFP-high tumours (serum concentration > 400 ng/ml), which represents an accepted prognostic cut-off and a predictor of response to ramucirumab. Those AFP-high tumours (18% of resected cases) were characterised by significantly lower AFP promoter methylation (p < 0.001), significant enrichment of progenitor-cell features (CK19, EPCAM), higher incidence of BAP1 oncogene mutations (8.5% vs 1.6%) and lower mutational rates of CTNNB1 (14% vs 30%). Specifically, AFP-high tumours displayed significant activation of VEGF signalling (p < 0.001), which might provide the rationale for the reported benefit of ramucirumab in this subgroup of patients.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Antibodies, Monoclonal, Humanized / therapeutic use
  • Biomarkers, Tumor / blood
  • Carcinoma, Hepatocellular / blood
  • Carcinoma, Hepatocellular / drug therapy
  • Carcinoma, Hepatocellular / genetics*
  • Clinical Trials as Topic
  • DNA Methylation
  • Humans
  • Liver Neoplasms / blood
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / genetics*
  • Promoter Regions, Genetic
  • alpha-Fetoproteins / analysis
  • alpha-Fetoproteins / genetics*
  • beta Catenin / genetics


  • Antibodies, Monoclonal, Humanized
  • Biomarkers, Tumor
  • CTNNB1 protein, human
  • alpha-Fetoproteins
  • beta Catenin
  • ramucirumab