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

2019; Springer Nature; Volume: 121; Issue: 4 Linguagem: Inglês

10.1038/s41416-019-0513-7

1532-1827

Robert Montal, Carmen Andreu-Oller, Laia Bassaganyas, Roger Esteban-Fabró, Sebastián Morán, Carla Montironi, Agrin Moeini, Roser Pinyol, Judit Peix, Laia Cabellos, Augusto Villanueva, Daniela Sia, Vincenzo Mazzaferro, Manel Esteller, Josep M. Llovet,

Cholangiocarcinoma and Gallbladder Cancer Studies

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.