Clinician scientists and scientists from the National Cancer Centre Singapore (NCCS) have found that epigenomics (changes in the way genes are switched on and off without changing the actual DNA sequence), may be the driving factor behind the development of the primary liver cancer, hepatocellular carcinoma (HCC). This discovery will help in the development of liver cancer treatment strategies in the future, as it supports using systemic and holistic approaches that evaluate tumours and their surrounding cellular environment. The novel findings were published in the journal JHEP Reports late last month.

The epigenome is fast becoming an important field of study in medical research. The epigenome, made up of chemical compounds and proteins that direct the genome, can provide clues into what drives genetic changes that cause cancer. HCC is highly heterogeneous and to date has no validated genetic biomarkers for therapeutic intervention. This makes it difficult to identify effective therapeutics for the disease. Studying the epigenome may be a potentially valuable way to shed light on how genetic changes drive HCC formation.

A research team from the National Cancer Centre Singapore (NCCS) analysed tumour samples from 30 patients with HCC using cutting-edge epigenomics technologies. Taking an orthogonal approach, which uses multiple analytical approaches to arrive at a conclusion, the team employed single cell RNA sequencing and bulk transcriptomics to validate epigenetic changes and study the surrounding cellular environment in depth.

Most significantly, the team were able to confirm that DNA mutations were not in fact major drivers of disease progression in HCC. Instead, they observed that patients with epigenetic changes that caused upregulation of specific signature genes showed a worse prognosis than those without those changes. Their results suggest that the epigenetics changes driven by metabolic changes in the tumour microenvironment were the driving factors of dysregulation in HCC. Moreover, the results also suggest that oncofoetal reprogramming in HCC, which was a novel immunosuppressive phenomenon reported by the same group previously, was underpinned by genome-wide enhancer rewiring.

“Our findings confirm that genetic changes in the DNA are not major drivers of liver cancer dysregulation, which may explain why, historically, we have not been able to identify genetic predictive biomarkers for hepatocellular carcinoma,” said senior author Professor Pierce Chow, Senior Consultant, Department of Hepato-Pancreato-Biliary and Transplant Surgery, Division of Surgery and Surgical Oncology, Singapore General Hospital and NCCS, and Vice Chair for Research for the Surgery Academic Clinical Programme, SingHealth Duke-NUS Academic Medical Centre.

The study findings provide a paradigm shift on how to approach the study of other cancers, in addition to liver cancer. Moving forward, the team plans to explore how the epigenome is affected by HCC-related diseases such as Hepatitis B induced HCC and non-viral HCC.

This research comes from one of the largest prospective cohorts for HCC known as the Precision Medicine in Liver Cancer across Asia-Pacific Network (PLANet 1.0) study, which has a cohort of patients from four countries in Asia. The work is also supported by a National Medical Research Council’s Clinician Scientist-Individual Research Grant.


Study reference: Jeon, A.-J., Anene-Nzelu, C. G., Teo, Y.-Y., Lee Chong, S., Sekar, K., Wu, L., Chew, S.-C., Chen, J., Kendarsari, R. I., Lai, H., Ling, W. H., Kaya, N. A., Lim, J. Q., Fui Chung, A. Y., Cheow, P.-C., Kam, J. H., Madhavan, K., Kow, A., Ganpathi, I. S., … Kah-Hoe Chow, P. (2023). A genomic enhancer signature associates with hepatocellular carcinoma prognosis. JHEP Reports.

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