Singapore, 13 December 2021 – Clinician scientists and scientists from the National Cancer Centre Singapore (NCCS) and A*STAR’s Genome Institute of Singapore (GIS), in collaboration with Singapore General Hospital (SGH), the National University Health System, Duke-NUS Medical School, Nanyang Technological University, and collaborators from China, Malaysia, Thailand and the Philippines, have described a dynamic genomic landscape of tumour heterogeneity in hepatocellular carcinoma (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) study. These novel findings from PLANet were recently published in the journal National Science Review (NSR).
Figure 1: Hepatocellular carcinomas (HCC) diversify during tumour evolution, leading to multiple co-existing subtypes in a significant proportion of HCC that will require combination systemic therapies to treat the disease.
Credit: A*STAR’s Genome Institute of Singapore
HCC is the seventh most common cancer worldwide, but the fourth leading cause of cancer death globally due to its high mortality rate. Strikingly, a disproportionate 80% of the disease burden is shouldered by Asian populations. Despite much effort, there is currently no validated predictive biomarker for systemic therapies in HCC and treatment efficacy remains poor. To address this unmet clinical need, a collaborative multi-disciplinary and multi-institutional team was awarded funding to establish the Translational and Clinical Research (TCR) Flagship Programme in Liver Cancer, which is supported with funding from the National Research Foundation Singapore and administered by the Singapore Ministry of Health’s National Medical Research Council (NMRC). In this programme, the PLANet study was initiated to enrol a prospective HCC patient cohort working with the Asia-Pacific Hepatocellular Carcinoma (AHCC) Trials Group across multiple Asian countries. Specifically, PLANet aims to understand molecular diversities within a tumour known as intra-tumour heterogeneity (ITH), as well as how we can use such understanding to guide patient stratification and treatment in HCC. In 2017, the group discovered that HCC has a wide range of genetic ITH across patients.
The study and its findings
The current study is based on a cohort of 67 patients from four Asian countries from the PLANet study and is the first study of ITH across multi-omic data layers (genome, transcriptome, immunome) in HCC. Researchers found variations in different regions of the same tumour for both genetic (DNA mutation) and transcriptomic (RNA expression) profiles. In particular, they found that the level of such variations differs across patients and over 30% of patients show a high transcriptomic ITH where a single tumour could contain multiple transcriptomic subtypes.
Such dynamic, evolutionary process in HCC helps to explain the poor response to systemic therapy in HCC, where therapies addressing only a single group of molecular targets is not sufficient. Using the PLANet cohort, the authors demonstrated how combination therapies can potentially address the high ITH to increase treatment response rates for HCC. Discoveries from this research provide novel scientific rationale for the development of innovative therapies for HCC. In the next phase, the group will focus on how to improve liver cancer treatment outcome by targeting this dynamically evolving heterogeneity.
The PLANet study has also provided researchers and clinicians an atlas to assess the evolutionary history of liver cancer. Such genomic information will provide a solid basis for understanding how individual patients might respond differently to drug treatments, thus enabling a precision medicine approach to treat patients differently in the future. Data from this study is now publicly available via the Singapore Oncology Data Portal (OncoSG) which allows integration, visualisation, analyses, and sharing of cancer genomics datasets generated in Singapore.
Dr Zhai Weiwei, a former principal investigator at GIS who co-led this work, noted, “This study depicted the first full landscape of tumour heterogeneity in HCC, providing a solid basis harnessing tumour evolution for patient prognosis and treatment”.
Professor Pierce Chow, senior author of the study, the overall principal investigator of PLANet and Senior Consultant, Department of Hepato-Pancreato-Biliary/Transplant Surgery, Division of Surgery and Surgical Oncology at SGH and NCCS said, “I have been treating HCC for more than 20 years and have conducted multi-national clinical trials in this cancer, but HCC remains a very challenging malignancy. Significant scientific breakthroughs are required to further improve patient outcomes and our current findings provide an important step in this direction.”
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About National Cancer Centre Singapore (NCCS)
The National Cancer Centre Singapore (NCCS) is a leading national and regional tertiary cancer centre with specialists who are experts in treating cancer. NCCS attends to the majority of cancer cases in Singapore’s public healthcare sector. 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 the 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 needs, the new NCCS building will be completed in 2022 with increased capacity and expanded facilities dedicated to cancer care, rehabilitation, research and education. To give patients the best treatment outcomes, NCCS will offer access to advanced and innovative treatment such as proton therapy at the new Goh Cheng Liang Proton Therapy Centre.
For more information, please visit: www.nccs.com.sg
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 write 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 the Agency for Science, Technology and Research (A*STAR)
A*STAR is Singapore's lead public sector R&D agency. Through open innovation, we collaborate with our partners in both the public and private sectors to benefit the economy and society. As a Science and Technology Organisation, A*STAR bridges the gap between academia and industry. Our research creates economic growth and jobs for Singapore, and enhances lives by improving societal outcomes in healthcare, urban living, and sustainability. A*STAR plays a key role in nurturing scientific talent and leaders for the wider research community and industry. A*STAR’s R&D activities span biomedical sciences to physical sciences and engineering, with research entities primarily located in Biopolis and Fusionopolis. For ongoing news, visit www.a-star.edu.sg.
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 Zhai, W. et al. Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in Hepatocellular Carcinoma: the PLANET study. Natl. Sci. Rev. (2021) doi:10.1093/nsr/nwab192
 Singal, A. G., Lampertico, P. & Nahon, P. Epidemiology and surveillance for hepatocellular carcinoma: New trends. J. Hepatol. 72, 250–261 (2020)
 SingHealth clinician scientists win national grant to research brain tumours, liver cancer. http://www.sgh.com.sg:80/news/awards/singhealth-clinician-scientists-win-national-grant-to-research-brain-tumours-liver-cancer
 Zhai, W. et al. The spatial organization of intra-tumour heterogeneity and evolutionary trajectories of metastases in hepatocellular carcinoma. Nat. Commun. 8, 4565 (2017)
National Science Review
Method of Research
Subject of Research
Human tissue samples
Dynamic phenotypic heterogeneity and the evolution of multiple RNA subtypes in Hepatocellular Carcinoma: the PLANET study