Research

Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide. 90% of HCC develops in patients with chronic liver disease (CLD); the causes of CLD are changing, with rapidly rising obesity and type 2 diabetes driving non-alcoholic fatty liver disease (NAFLD). Patients with CLD form a clear at-risk population for HCC development, amenable to early detection. The liver in CLD is marked by a cancerisation field effect; the mechanistic basis of this field effect is unknown.

We hypothesised that it could be encoded at HCC-associated genomic loci. We used whole genome sequencing of non-malignant human CLD tissue, but did not find HCC-associated driver mutations. We identified recurrent somatic mutations in several disease-relevant genes, including FOXO1 (insulin and AMPK signalling) and ACVR2A (activin signalling), with evidence of convergent evolution in the same liver. Mutations in FOXO1 are at a single AMPK phospho-site and we have found that these mutations are functional.

We have produced an AudioPod explaining our research that you can listen to here.

Aims

We aim to understand the role of these recurrent somatic mutations in the cancerisation field effect of CLD, to understand HCC development. We hypothesise they will be:

1) Functional in diseased hepatocytes, leading to mechanistic insights into HCC pathogenesis;

2) Functional in mouse models of CLD, modulating development of HCC;

3) Identifiable in CLD patients, with potential as diagnostic and prognostic biomarkers.