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.
Highlights
The global disease burden of hepatocellular carcinoma (HCC) is increasing worldwide, with an estimated 50% of cases receiving systemic treatments for advanced stage.[1,2] In the last 2 years, several compounds have shown clinical efficacy in the first-(lenvatinib) or second-line setting and joined the standard of care, sorafenib, leading to a median survival of 2 years with sequential therapies.[1]
For the purpose of the study, we analysed the molecular profiles of 520 HCC human samples with available baseline AFP serum concentrations, including an internal cohort of 244 surgically resected fresh frozen samples (HEPTROMIC data set),[5] and an external publicly available cohort of 276 primary HCC from The Cancer Genome Atlas (TCGA data set)[6] (Supplementary Fig. 1)
AFP serum concentrations followed a logarithmic distribution in our internal HEPTROMIC cohort, with values ranging from 0 to 71770 ng/ml (Supplementary Fig. 2A)
Summary
The global disease burden of hepatocellular carcinoma (HCC) is increasing worldwide, with an estimated 50% of cases receiving systemic treatments for advanced stage.[1,2] In the last 2 years, several compounds have shown clinical efficacy in the first-. (lenvatinib) or second-line (regorafenib, cabozantinib) setting and joined the standard of care, sorafenib, leading to a median survival of 2 years with sequential therapies.[1] Ramucirumab, a monoclonal antibody against VEGFR2, is the first drug to demonstrate efficacy in a biomarker-driven phase III trial in HCC, showing a survival benefit as second-line treatment in those patients with alpha-fetoprotein (AFP) serum levels higher than 400 ng/ml.[3] the rationale behind the use of AFP as a predictive biomarker is not fully understood. In HCC, AFP serum concentration may vary from normal (< 10 ng/ml) to extremely high (>100000 ng/ml).[2,4]
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