Researchers Uncover Liver Disease-Linked Hepatocyte State That Could Predict Cancer Risk

A transcriptional state that is only present in diseased liver cells and can be used to predict hepatocellular carcinoma (HCC) risk is reported in Cell Genomics this week. HCC, the most common histologic type of liver cancer, develops secondary to chronic liver disease. Yet only a minority of liver disease patients will develop HCC, underscoring the importance of identifying those at high risk for the cancer. A team led by Curtin University scientists used single-nucleus RNA sequencing to characterize the cellular microenvironment of healthy and pre-malignant livers in two different mouse models. They uncovered a previously uncharacterized disease-associated hepatocyte transcriptional state — dubbed daHep — and show that daHep cells are absent in healthy livers but increasingly prevalent as chronic liver disease progresses. Further analyses showed that daHep-enriched tissue regions are riddled with structural variants, suggesting that the cells represent a premalignant intermediary, and that a similar phenotype exists in chronic human liver disease. Importantly, elevated daHep levels were found to precede carcinogenesis and predict a higher risk of HCC development in mice, a finding that was confirmed in humans through a retrospective analysis of a hepatitis C virus-driven HCC cohort. "The discovery of daHeps as a highly predictive biomarker provides us with a clinically significant opportunity to triage liver disease patients into low-risk and high-risk groups," the study's authors write. "This facilitates a more focused clinical follow-up, rationalization of clinical resource consumption, earlier diagnosis, and improved cancer outcomes in the small percentage of individuals who develop tumors each year."