By Gilang Cahya 
Researchers from leading international institutions have made a significant discovery linking age-related genetic changes in blood cells to poorer prognoses in cancer patients. A new study, published in the prestigious New England Journal of Medicine, reveals that the expansion of mutant blood cells, a phenomenon known as clonal haematopoiesis of indeterminate potential (CHIP), can infiltrate solid tumours and is associated with an increased risk of cancer relapse and mortality. This groundbreaking research, conducted by scientists from the Francis Crick Institute, University College London (UCL), Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK), sheds new light on the complex interplay between ageing, genetics, and cancer progression.
The Pervasive Influence of Ageing on Cellular Health
The global population is aging, and with this demographic shift comes an increased prevalence of age-related diseases, including cancer and cardiovascular conditions. Understanding the fundamental biological processes that underpin these diseases is paramount for developing effective preventative strategies and treatments. One such process is the accumulation of genetic mutations in our cells over time, a natural consequence of aging and exposure to environmental factors.
Clonal haematopoiesis of indeterminate potential (CHIP) represents a state where blood stem cells acquire mutations. While CHIP has previously been recognized as a risk factor for age-related disorders, including cardiovascular disease, its specific impact on the evolution and progression of solid tumours has remained an area requiring deeper investigation. This new study directly addresses this knowledge gap by examining over 400 lung cancer patients enrolled in Cancer Research UK-funded TRACERx and PEACE studies, and an expansive cohort of 49,000 patients with various cancer types from MSK.
Unveiling the Link: CHIP and Cancer Prognosis
The initial phase of the research involved analyzing blood samples from patients to identify the presence of CHIP mutations. When correlated with clinical data, a stark pattern emerged: patients with these blood cell mutations had a significantly shorter lifespan, irrespective of their age at diagnosis or the stage of their cancer. This finding alone underscored the potential significance of CHIP in influencing cancer outcomes.
However, the investigation did not stop at the presence of CHIP in the blood. The researchers delved deeper to determine if these specific mutations were also present within the patients’ solid tumours, specifically lung tumours, due to the infiltration of mutated blood cells. Their analysis revealed that in 42% of CHIP patients, these mutations were indeed found within their tumours. The scientists coined this phenomenon "tumour infiltrating clonal haematopoiesis" (TI-CH). Crucially, it was TI-CH, rather than CHIP alone, that demonstrated a robust association with a higher risk of cancer recurrence and death.
This critical observation was further corroborated by data from the PEACE study, which involved postmortem investigations of metastatic sites – the areas where cancer spreads and is the primary cause of cancer-related fatalities. The findings indicated that metastatic tumours frequently harboured TI-CH mutations, reinforcing the link between these age-related blood cell changes and aggressive cancer spread.
Not All Mutations are Equal: The Role of Myeloid Cells
To further elucidate the mechanisms by which TI-CH contributes to poor patient outcomes, the research team meticulously examined the cellular composition of lung tumours. They discovered that patients with TI-CH exhibited an expansion of myeloid cells within their tumours. Myeloid cells are a type of immune cell that plays a crucial role in the tumor microenvironment. Unlike other immune cells that are programmed to detect and destroy cancer, myeloid cells are known to modulate inflammation and can actively promote tumour growth and metastasis.
The study also highlighted that specific mutations, particularly those affecting the TET2 gene, played a pivotal role. The TET2 gene is critical for regulating blood cell production. In thousands of individuals analyzed, blood cells carrying TET2 mutations were found to be more prone to infiltrating tumours. Through detailed single-cell analysis of hundreds of cells from the tumours of two TI-CH patients, the researchers confirmed that TET2 mutations were predominantly located within myeloid cells, and not other immune cell types, suggesting a specific tropism for these cells.
In a significant experimental validation, researchers collaborated with blood cancer and CHIP experts at the Crick Institute, led by Dominique Bonnet. They successfully generated organoids, essentially miniature tumours grown in a lab, incorporating TET2-mutant myeloid cells. Their experiments demonstrated that these TET2-mutant myeloid cells actively remodeled the tumor microenvironment and accelerated the growth of the lung tumour organoids, providing direct evidence of their oncogenic potential.
Broadening the Scope: Implications Beyond Lung Cancer
The implications of these findings extend beyond lung cancer. In collaboration with researchers at Memorial Sloan Kettering Cancer Center in the United States, the team leveraged a vast dataset of over 49,000 patients across various cancer types. This large-scale analysis confirmed that the presence of TI-CH was an independent predictor of shorter survival.
Furthermore, the study revealed variations in the prevalence of CHIP and TI-CH across different cancer types. These age-related blood cell mutations were found to be more common in cancers that are notoriously difficult to treat, such as lung cancer, head and neck cancers, and pancreatic cancer. This observation suggests that TI-CH may represent a significant driver of aggressive disease in these challenging malignancies.
Future Directions and Potential Interventions
The next crucial steps for this research involve definitively confirming that CHIP directly contributes to cancer outcomes and meticulously detailing the precise biological mechanisms through which CHIP functionally influences the development of aggressive cancers. This deeper understanding could pave the way for novel therapeutic strategies.
Oriol Pich, a Postdoctoral Project Research Scientist at the Crick’s Cancer Evolution and Genome Instability Laboratory and a lead author on the study, emphasized the significance of their findings. "Our results show that blood cells carrying age-related mutations can infiltrate tumours and impact cancer evolution, leading to worse outcomes for patients," Pich stated. "This is important because CHIP is a natural phenomenon of ageing that is common in patients with cancer."
Charlie Swanton, Deputy Clinical Director at the Crick, Chief Clinician at Cancer Research UK, and Chief Investigator for the TRACERx study, highlighted the broader impact. "This is the first time that we’ve been able to see at scale, the interaction of two different types of ‘clonal proliferations’, age-related CHIP and cancer, providing insight into how ageing might impact cancer risk," Swanton remarked. "As we start to piece together the picture of the most important mutations which evolve during the ageing process in cells from the bone marrow, and the impact they have in disease, we hope we can start to identify opportunities for intervention and maybe even prevention of some age-related cancers."
The research was generously supported by Cancer Research UK and the National Institute of Health and Care Research UCLH Biomedical Research Centre, alongside other funding bodies. This collaborative effort represents a significant leap forward in understanding the intricate relationship between aging and cancer, opening new avenues for research and potentially leading to improved patient care and earlier interventions. The identification of TI-CH as a key factor in cancer progression suggests that targeting these age-related cellular changes might offer a novel therapeutic approach for a range of difficult-to-treat cancers.
