Towards more personalised management of liver cancer

Liver cancer is the second cause of cancer-related death globally. The incidence of the disease is increasing, with more than 850 000 new cases per year worldwide. Hepatocellular carcinoma (HCC) is the most prevalent form of liver cancer accounting for 90 % of cases. Only one third of newly diagnosed patients are eligible for curative treatments and the overall poor survival rates necessitate the urgent development of novel regimens.

The EU-funded HEPTROMIC (Genomic predictors and oncogenic drivers in hepatocellular carcinoma) initiative aimed to address important aspects of HCC biology. The objectives were to define biomarkers for identification of HCC patients with poor prognosis, and novel genetic or epigenetic drivers that are critical for a more personalised therapeutic approach.

HEPTROMIC collected 637 samples from 270 patients with tumours and normal livers and annotated them with clinical variables. Analysis at the transcriptomic level (mRNA and miRNA) of tumour and adjacent tissues was used to develop a composite prognostic model for HCC recurrence. Importantly, the adjacent non-tumour cirrhotic tissue also provided complementary prognostic information of tumour signatures.

Based on mRNA data, researchers defined so-called 5-gene score associated with specific survival times of patients with resected HCC independent of other clinical features of the tumours. This 5-gene score in combination with the expression pattern of 186 genes in adjacent tissues increased total prognostic accuracy. Profiling of the miRNA provided further characterisation of the HCC subclasses with poor prognosis in addition to mRNA-based classification.

Investigation of epigenetic regulation of gene expression of HCC samples and adjacent tissues allowed the generation of methylation signature based on 36 probes with independent prognostic value. Importantly, patients with this methylation profile displayed mRNA signatures of tumours with progenitor cell features.

Finally, partners performed massive parallel sequencing in 250 samples and obtained the total mutational landscape of HCC and identified novel mutational signatures related to tobacco consumption. They also provided in vitro and in vivo data demonstrating the role of the insulin-like growth factor pathway in hepatocarcinogenesis and as mechanism of sorafenib resistance.

HEPTROMIC represents an important step towards effective clinical translation of research findings. Refinement of the risk stratification of patients according to solid biomarkers will lead to an improvement in the treatment outcome of HCC.