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

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

Author information

1
Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain.
2
Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet, Barcelona, Catalonia, Spain.
3
Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
4
University of Milan and Gastrointestinal Surgery and Liver Transplantation Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
5
Centro de Investigación Biomédica en Red Cancer (CIBERONC), Madrid, Spain.
6
Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain.
7
Physiological Sciences Department, School of Medicine and Health Sciences, University of Barcelona (UB), Barcelona, Catalonia, Spain.
8
Josep Carreras Leukaemia Research Institute (IJC), Badalona, Barcelona, Catalonia, Spain.
9
Translational Research in Hepatic Oncology, Liver Unit, IDIBAPS, CIBERehd, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain. jmllovet@clinic.cat.
10
Liver Cancer Program, Division of Liver Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA. jmllovet@clinic.cat.
11
Institucio Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Catalonia, Spain. jmllovet@clinic.cat.

Abstract

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.

PMID:
31285588
PMCID:
PMC6738090
[Available on 2020-07-09]
DOI:
10.1038/s41416-019-0513-7
[Indexed for MEDLINE]
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