• Hepatocellular carcinoma (HCC) is the only common solid organ cancer without any validated predictive biomarkers and has one of the highest mortality rates amongst all cancers. 
  • A seminal new study discovered significant heterogeneity across patient tumours, and more strikingly, the pervasive co-existence of multiple molecular subgroups even within the same tumours, where the most aggressive subgroup determines disease outcome. 
Singapore, 24 June 2024 – A study led by clinician-scientists and scientists from the National Cancer Centre Singapore (NCCS) and A*STAR’s Genome Institute of Singapore (GIS) and funded by the National Research Foundation Singapore (NRF) has discovered unexpected molecular heterogeneity even within the same liver tumours. More than 40% of HCC harbours more than one molecular subtype within the same tumour and in these, the clinical outcomes for the patients are best predicted by the most aggressive subtype. This phenomenon, termed the “bad apple effect”, has significant implications on the understanding of liver cancer and suggests that a more holistic sampling of liver cancer tumours, is needed to improve the way the disease is studied and treated to optimise patient outcomes. These new findings were published in the Journal of Hepatology on 21 May 2024. 

In Singapore, liver cancer is the third most common cause of cancer deaths in males and fifth most common cause in females1. HCC, the most common type of primary liver cancer, is the only common solid organ cancer without any validated predictive biomarkers. This means that doctors are unable to use molecular biomarkers to determine which drug is best for an individual patient with HCC. This is one of the reasons why treatment is less effective compared to other common cancers. The case-fatality ratio of HCC today is 0.92—the highest amongst all cancers in Asians.2

To address this unmet clinical need and improve the treatment of HCC, the PLANet study (Precision Medicine in Liver Cancer across an Asia-Pacific Network), analysed over 600 tumour and adjacent normal samples that were surgically resected from 123 HCC patients from Singapore, Malaysia, Thailand and the Philippines. Samples were analysed using multi-regional sampling approach that enables deep profiling of genomic and cellular heterogeneity within each tumour to evaluate their impact on disease progression. This study is supported by NRF under the National Medical Research Council (NMRC) Open Fund-Large Collaborative Grant and administered by the Singapore Ministry of Health through the NMRC Office, MOH Holdings Pte Ltd. 

The team found that there was unexpected intratumoural heterogeneity in the HCC transcriptome, also known as the RNA transcript, which determines the behaviour of tumour cells. This indicates that the current practice of obtaining a single sample from liver cancer tumours under-represents the complexity of the tumour significantly and limits a comprehensive understanding of the entire tumour ecosystem. This heterogeneity may explain why developing therapeutics for HCC is a challenge as it cannot be treated by a one-size-fits all approach. 

The second key finding was that more than 40% of HCC samples analysed harboured more than one transcriptomic subtype. Of these, the subtype with the worse prognosis determined each individual patient’s clinical trajectory and outcome. This is the first time this “bad apple effect” has ever been shown in HCC. The team also found that early and late tumour evolution characteristics were important in predicting patients’ survival. 

“Uncovering the “bad apple effect” in liver cancer progression has generated an important blueprint for HCC that can be used to improve the treatment of the disease. Our study shows a comprehensive landscape of evolutionary history of the disease and is a rich resource for understanding tumour heterogeneity and clinical progression,” said Professor Pierce Chow, Corresponding Principal Investigator of PLANet 2.0, senior author of the study and Senior Consultant Surgeon, Division of Surgery and Surgical Oncology, Singapore General Hospital and NCCS. 

“The application of genomic technologies has enabled us to produce a high-resolution map of the different cell types that co-exist within the same tumour. Now, clinicians are able to pinpoint the specific cell populations which have a more deterministic role in driving the disease and develop therapeutic approaches to target the more aggressive cells in future,” said Associate Professor Tam Wai Leong, Theme PI of PLANet 2.0, co-senior author of the study and Deputy Executive Director at A*STAR’s GIS. 

The group received a S$25 million grant to conduct PLANet 2.0, under the NMRC Open Fund-Large Collaborative Grant programme in 2022, and now includes collaborators from A*STAR’s Institute of Molecular and Cell Biology and Duke-NUS Medical School. The team has continued their studies by using a spatial transcriptomics and spatial metabolomics approach in two therapeutic studies to understand the HCC microenvironment. This approach has found that co-localisation of biomarkers is important to the biology of HCC and will be key to making progress in the development and discovery of novel and more effective treatments for HCC. 

1National Registry of Diseases Office. (2023, Aug). Singapore Cancer Registry Annual Report 2021. 
2Rumgay H, Arnold M, Ferlay J, Lesi O, Cabasag CJ, Vignat J, et al. Global burden of primary liver cancer in 2020 and predictions to 2040. J Hepatol. 2022 Dec;77(6):1598–606.

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Study: Chen, J.*, Kaya, N. A., Zhang, Y., Kendarsari, R. I., Sekar, K., Lee Chong, S., Seshachalam, V. P., Ling, W. H., Jin Phua, C. Z., Lai, H., Yang, H., Lu, B., Lim, J. Q., Ma, S., Chew, S. C., Chua, K. P., Alvarez, J. J. S., Wu, L., Ooi, L., Chung, A. Y., Cheow, P. C., Kam, J. H., Kow, A. W., Ganpathi, I. S., Bunchaliew, C., Thammasiri, J., Koh, P. S., Ong, D. B., Lim, J., Villa, V. H., Cruz, R. D., Loh, T. J., Wan, W. K., Leow, W. Q., Yang, Y., Liu, J., Skanderup, A. J., Pang, Y. H., Soon, G. S., Madhavan, K., Lim, T. K., Bonney, G., Goh, B. K., Chew, V., Dan, Y. Y., Toh, H. C., Foo, R. S., Tam, W. L.*, Zhai, W.*, & Chow, P. K.* (2024). A multimodal atlas of hepatocellular carcinoma reveals convergent evolutionary paths and 'bad apple' effect on clinical trajectory. Journal of hepatology, S0168-8278(24)00352-0. *Corresponding authors Advance online publication. https://doi.org/10.1016/j.jhep.2024.05.017  

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For media enquiries, please contact: 
Dharshini Subbiah
National Cancer Centre Singapore
Corporate Communications
Email : dharshini.subbiah@nccs.com.sg 

Eliza Lim (Ms)
Senior Manager, Office of Corporate Communication and Office of Research Planning
A*STAR’s Genome Institute of Singapore (GIS)
Email: Eliza_Lim@gis.a-star.edu.sg 

Nur Amin (Mr)
Deputy Head
Corporate Communications Division
National Research Foundation
Email: nur_amin@nrf.gov.sg 

About the National Cancer Centre Singapore 
The National Cancer Centre Singapore (NCCS) is a leading national and regional tertiary cancer centre with specialists who are experts in treating cancer. In addition to offering holistic and multidisciplinary oncology care, our clinicians and scientists collaborate with local and international partners to conduct robust, cutting-edge clinical and translational research. To achieve its vision of being a global leading cancer centre, NCCS offers world-class care and shares its depth of experience and expertise by training local and overseas medical professionals. 

To meet growing healthcare needs, the new NCCS building opened in 2023 with increased capacity and expanded facilities dedicated to cancer care, rehabilitation, research and education. To give patients the best treatment outcomes, advanced and innovative treatment such as proton therapy is offered at the new Goh Cheng Liang Proton Therapy Centre at NCCS. 

In 2024, NCCS celebrates its silver anniversary, celebrating 25 years of advancing cancer care from breakthroughs to healing. 

About A*STAR’s Genome Institute of Singapore (GIS) 
The Genome Institute of Singapore (GIS) is an institute of the Agency for Science, Technology and Research (A*STAR). It has a global vision that seeks to use genomic sciences to achieve extraordinary improvements in human health and public prosperity. Established in 2000 as a centre for genomic discovery, the GIS pursues the integration of technology, genetics, and biology towards academic, economic and societal impact, with a mission to "read, reveal and (ω)rite DNA for a better Singapore and world". 

Key research areas at the GIS include Precision Medicine & Population Genomics, Genome Informatics, Spatial & Single Cell Systems, Epigenetic & Epitranscriptomic Regulation, Genome Architecture & Design, and Sequencing Platforms. The genomics infrastructure at the GIS is also utilised to train new scientific talent, to function as a bridge for academic and industrial research, and to explore scientific questions of high impact. 

For more information about GIS, please visit www.a-star.edu.sg/gis. 

About National Research Foundation 
The National Research Foundation, Singapore (NRF), set up on 1 January 2006, is a department within the Prime Minister’s Office. The NRF sets the national direction for research and development (R&D) by developing policies, plans and strategies for research, innovation and enterprise. It also funds strategic initiatives and builds up R&D capabilities by nurturing research talent. 

Learn more about the NRF at www.nrf.gov.sg. 

About the National Medical Research Council (NMRC) 
The NMRC was established in 1994 to oversee research funding from the Singapore Ministry of Health (MOH) and support the development and advancement of biomedical research in Singapore, particularly in the public healthcare clusters and medical schools. NMRC engages in research strategy and planning, provides funding to support competitive research grants and core research enablers, and is responsible for the development of clinician scientists through awards and fellowships. The council’s work is supported by the NMRC Office which is part of MOH Holdings Pte Ltd. Through its management of the various funding initiatives, NMRC promotes healthcare research in Singapore, for better health and economic outcomes.