From sweet, red Fuji apples to the tart, green Granny Smith, apples come in many varieties. Similarly, tumour cells in hepatocellular carcinoma (HCC)—the most common primary liver cancer—can be a mixed bag, differing in their genes and behaviour. Unlike apples, however, these cells can evolve rapidly, taking on new mutations that shape a patient’s fate.
“By studying tumour evolution, we can reveal what drives HCC’s clinical trajectories: its likely recurrence, spread to other body parts (metastasis) and resistance to therapies,” said Wai Leong Tam, Deputy Executive Director at the A*STAR Genome Institute of Singapore (A*STAR GIS).
Tam added that HCC remains the only common solid organ cancer without any validated predictive biomarkers, making it more difficult to treat than others. Such indicators could otherwise help doctors determine which drugs are best for a specific patient, as what works for some HCC cells may not on others.
To uncover the links between HCC tumour evolution and patient outcomes, a multinational research team embarked on the Precision Medicine in Liver Cancer across an Asia-Pacific Network (PLANet 1.0) cohort study.
The PLANet 1.0 team included Tam and senior author Pierce Chow of the National Cancer Centre Singapore (NCCS), with colleagues from A*STAR GIS; the A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB); NCCS; Duke-NUS Medical School, Singapore; as well as research hospitals and institutes from Singapore, Thailand, the US, Malaysia and the Philippines.
This study delved into tumours resected from 123 treatment-naïve patients with HCC from four Asian countries. Where prior studies had relied on single samples from tumours, PLANet 1.0 used multi-region samples to capture each tumour’s complexity. These were subjected to cutting-edge genomic and transcriptomic analyses, then matched with clinical parameters to create an unprecedented view of HCC tumour composition and evolution.
One key finding was that HCC tumour cells had different gene expression patterns that could be broadly grouped into six distinct subtypes. These subtypes varied not just across tumours, but within them: more than 40 percent of tumours analysed in PLANet 1.0 were comprised of two or more subtypes.
“This heterogeneity may explain why developing therapeutics for HCC is a challenge, as it cannot be treated by a one-size-fits all approach,” explained A*STAR GIS postdoctoral fellow Ying Zhang, who is one of the study’s lead authors.
Strikingly, while the subtypes seemed linked to both tumour aggressiveness and patient prognoses, the team found that in tumours with mixed subtypes, the most aggressive subtype present was the best predictor of patient outcomes—much like how ‘one bad apple spoils the barrel’.
“Uncovering this ‘bad apple effect’ in liver cancer progression has generated an important blueprint for HCC that can be used to improve treatment of the disease,” said Chow.
The team also found that more aggressive molecular subtypes appeared to share common genetic origins, such as dual mutations in the genes TP53 and TERT, or TP53 and beta-catenin. Hence, targeting these pathways could represent a therapeutic strategy to disrupt the ‘bad apple’ subtypes.
Springboarding off PLANet 1.0’s success, the team received a S$25 million grant under Singapore’s National Medical Research Council to conduct PLANet 2.0, which aims to probe the ‘bad apple’ effect further in patients receiving immunotherapy for HCC.
The A*STAR-affiliated researchers contributing to this research are from the A*STAR Genome Institute of Singapore (A*STAR GIS) and A*STAR Institute of Molecular and Cell Biology (A*STAR IMCB).
