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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.

The authors have established a method for the analysis of gene expression in tissue specimens preserved in formaldehyde. The expression profile of tissue adjacent to primary hepatocellular carcinoma, rather than the cancer itself, is associated with late recurrence. This finding, together with other data, suggests that the late recurrences are actually second primary tumors. The gene expression profile of tissue adjacent to primary hepatocellular carcinoma, rather than the cancer itself, is associated with late recurrence. This finding, together with other data, suggests that the late recurrences are actually second primary tumors. In developing countries, hepatocellular carcinoma often comes to medical attention when the tumors are at an advanced stage and curative therapies are of limited benefit. In developed countries, however, at-risk populations of patients (e.g., those who are infected with hepatitis virus and have cirrhosis) are often under close surveillance; as a result, hepatocellular carcinoma is usually detected when the tumors are small and treatment is more likely to be successful. 1 , 2 Nevertheless, recurrences eventually occur in most patients. 1 , 2 Studies suggest that chemopreventive strategies may suppress recurrence and prolong survival, 1 , 3 – 6 although these findings are still uncertain. It would . . .

ObjectiveSorafenib is effective in hepatocellular carcinoma (HCC), but patients ultimately present disease progression. Molecular mechanisms underlying acquired resistance are still unknown. Herein, we characterise the role of tumour-initiating cells (T-ICs) and signalling pathways involved in sorafenib resistance.DesignHCC xenograft mice treated with sorafenib (n=22) were explored for responsiveness (n=5) and acquired resistance (n=17). Mechanism of acquired resistance were assessed by: (1) role of T-ICs by in vitro sphere formation and in vivo tumourigenesis assays using NOD/SCID mice, (2) activation of alternative signalling pathways and (3) efficacy of anti-FGF and anti-IGF drugs in experimental models. Gene expression (microarray, quantitative real-time PCR (qRT-PCR)) and protein analyses (immunohistochemistry, western blot) were conducted. A novel gene signature of sorafenib resistance was generated and tested in two independent cohorts.ResultsSorafenib-acquired resistant tumours showed significant enrichment of T-ICs (164 cells needed to create a tumour) versus sorafenib-sensitive tumours (13 400 cells) and non-treated tumours (1292 cells), p<0.001. Tumours with sorafenib-acquired resistance were enriched with insulin-like growth factor (IGF) and fibroblast growth factor (FGF) signalling cascades (false discovery rate (FDR)<0.05). In vitro, cells derived from sorafenib-acquired resistant tumours and two sorafenib-resistant HCC cell lines were responsive to IGF or FGF inhibition. In vivo, FGF blockade delayed tumour growth and improved survival in sorafenib-resistant tumours. A sorafenib-resistance 175 gene signature was characterised by enrichment of progenitor cell features, aggressive tumorous traits and predicted poor survival in two cohorts (n=442 patients with HCC).ConclusionsAcquired resistance to sorafenib is driven by T-ICs with enrichment of progenitor markers and activation of IGF and FGF signalling. Inhibition of these pathways would benefit a subset of patients after sorafenib progression.