By Gilang Cahya 
Researchers from a consortium of leading institutions, including the Francis Crick Institute, University College London (UCL), Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK), have uncovered a significant link between age-related changes in blood cells and the progression of cancer. Their groundbreaking study, published in the New England Journal of Medicine, reveals that the expansion of mutated blood cells, a phenomenon known as Clonal Haematopoiesis of Indeterminate Potential (CHIP), can infiltrate cancerous tumours and is associated with poorer prognoses for patients. This discovery offers crucial insights into the complex interplay between ageing and cancer development, potentially paving the way for new therapeutic strategies.
Understanding the Ageing-Cancer Nexus
The biological interface between age-related genetic alterations and diseases prevalent in older populations, such as cancer and cardiovascular disease, represents a critical frontier in medical research. As global populations age, understanding these connections becomes paramount for developing effective preventative and therapeutic interventions. CHIP, a condition characterized by the accumulation of mutations in blood stem cells over time, is influenced by both the natural ageing process and environmental factors. While CHIP has previously been linked to an increased risk of age-related disorders, its precise impact on the evolution and prognosis of solid tumours has remained less explored until now.
Unveiling Tumour-Infiltrating Clonal Haematopoiesis (TI-CH)
The extensive study involved a comprehensive analysis of over 400 lung cancer patients enrolled in Cancer Research UK funded TRACERx and PEACE studies, alongside a massive dataset of 49,000 patients with various cancer types from MSK. Initially, researchers examined blood samples to identify individuals with CHIP mutations. By correlating this genetic information with clinical data, they observed that the presence of these mutations was associated with a significantly shorter survival time, irrespective of the patient’s age or the stage at which their cancer was diagnosed.
The investigation then delved deeper, seeking to determine if these CHIP mutations were also present within the lung tumours themselves, likely due to the infiltration of mutated blood cells. This phenomenon, termed tumour-infiltrating clonal haematopoiesis (TI-CH), was identified in a substantial 42% of patients with CHIP. Crucially, the study found that it was TI-CH, rather than CHIP alone, that was directly linked to an elevated risk of cancer relapse and mortality.
This critical finding was further corroborated by data from the PEACE study, a post-mortem investigation focused on metastatic sites – the areas where cancer spreads and a primary cause of cancer-related deaths. The analysis revealed that metastatic tumours at these sites frequently harboured TI-CH mutations, underscoring the role of these age-related blood cell changes in driving advanced disease.
Differentiating Mutation Impact and the Role of TET2
The research team further investigated the mechanisms by which TI-CH contributes to poor patient outcomes by examining the cellular composition of lung tumours. They discovered that patients with TI-CH exhibited an expansion of myeloid cells, a type of immune cell within the tumour microenvironment. Unlike some immune cells that are programmed to detect and combat cancer, myeloid cells play a complex role in regulating inflammation and have been implicated in supporting tumour progression and metastasis.
A significant discovery emerged when the scientists focused on mutations affecting the TET2 gene. This gene is a vital regulator of blood cell production. Their analysis, spanning thousands of individuals, indicated that blood cells with TET2 mutations were more prone to infiltrate tumours. Further examination of hundreds of individual cells from the tumours of two patients with TI-CH confirmed that TET2 mutations were predominantly found in myeloid cells, with a negligible presence in other immune cell types.
In a collaborative effort with blood cancer and CHIP experts at the Crick, led by Dominique Bonnet, the team conducted experimental studies to elucidate the impact of TET2 mutations. They successfully grew organoids – miniature, three-dimensional models of lung tumours – in the presence of TET2 mutant myeloid cells. These experiments demonstrated that these mutant myeloid cells could actively remodel the tumour microenvironment and accelerate the growth of the tumour organoids.
Broadening the Scope: Insights Across Cancer Types
The research extended its reach beyond lung cancer, collaborating with researchers at Memorial Sloan Kettering Cancer Center to validate their findings in a much larger cohort of over 49,000 patients across diverse cancer types. This extensive analysis confirmed that the presence of TI-CH served as an independent predictor of reduced survival. However, the prevalence of both CHIP and TI-CH varied significantly across different cancer types. The study identified these mutations as being more common in cancers that are notoriously difficult to treat, including lung cancer, head and neck cancers, and pancreatic cancer.
Future Directions and Clinical Implications
The implications of this research are far-reaching. The next critical steps involve confirming the direct causal contribution of CHIP to cancer outcomes and meticulously detailing the exact molecular mechanisms by which CHIP functionally influences the development of aggressive cancers.
Oriol Pich, a Postdoctoral Project Research Scientist at the Crick’s Cancer Evolution and Genome Instability Laboratory and one of the study’s lead authors, emphasized the significance of these findings. "Our results demonstrate that blood cells carrying age-related mutations can infiltrate tumours and profoundly impact cancer evolution, leading to worse outcomes for patients," Pich stated. "This is particularly important because CHIP is a natural phenomenon of ageing that is already 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 unprecedented nature of this work. "This is the first time we’ve been able to observe at scale the interaction of two distinct types of ‘clonal proliferations’ – age-related CHIP and cancer," Swanton remarked. "This provides invaluable insight into how ageing might influence cancer risk." He further expressed optimism about future applications: "As we begin to piece together the puzzle of the most critical mutations that emerge during the ageing process in bone marrow cells, and their impact on disease, we hope to identify opportunities for intervention and potentially even prevention of certain age-related cancers."
The research was supported by substantial funding from Cancer Research UK and the National Institute of Health and Care Research UCLH Biomedical Research Centre, alongside contributions from additional funders, underscoring the collaborative and resource-intensive nature of this significant scientific endeavour.
Broader Context and Historical Precedent
The investigation into the link between ageing and cancer is not new, but this study provides a critical mechanistic link through the identified role of CHIP and TI-CH. For decades, oncologists and researchers have observed that older individuals are at a significantly higher risk of developing cancer. This has been attributed to a multitude of factors, including accumulated DNA damage from environmental exposures over a lifetime, declining immune surveillance, and alterations in cellular repair mechanisms. However, identifying specific cellular drivers that bridge the gap between the ageing process and cancer progression has been a major challenge.
CHIP was first described in the early 2000s, with early research focusing on its association with hematologic malignancies like leukemia. Over the past decade, its link to non-hematologic conditions, particularly cardiovascular disease, has become increasingly evident. The TRACERx study, initiated in 2010, has been a landmark longitudinal study investigating the evolutionary pathways of lung cancer, providing a rich dataset for understanding tumour heterogeneity and its impact on treatment response. The PEACE study, a complementary initiative, focuses on the terminal stages of cancer and the mechanisms of metastasis. The integration of data from these large-scale initiatives with the extensive cancer registry data from MSK has provided the statistical power and breadth necessary to make such significant discoveries.
The identification of myeloid cell expansion and the specific role of TET2 mutations adds another layer of complexity to our understanding of the tumour microenvironment. Myeloid-derived suppressor cells (MDSCs), a subset of myeloid cells, are well-known for their immunosuppressive properties within the tumour. The finding that TET2 mutant myeloid cells can actively remodel this environment and promote tumour growth suggests a direct, pro-tumorigenic function beyond mere infiltration. This opens up avenues for therapeutic strategies targeting these specific cell populations or their signalling pathways within the tumour microenvironment.
The implications for clinical practice could be profound. If CHIP or TI-CH can be reliably detected and quantified, they could serve as important prognostic biomarkers, helping clinicians stratify patients and tailor treatment intensity. Furthermore, understanding the mechanisms by which these mutated blood cells influence cancer could lead to the development of novel therapeutic interventions. These might include drugs that target the expanded myeloid cell populations, interfere with their pro-tumorigenic signaling, or even strategies to prevent or reverse the accumulation of age-related mutations in blood stem cells.
The research team’s commitment to further investigation underscores the ongoing nature of scientific discovery. Establishing a definitive causal link and unraveling the precise molecular pathways will be crucial for translating these findings into tangible benefits for patients. As the global population continues to age, the insights gained from this study offer a beacon of hope for improving cancer prevention, diagnosis, and treatment in the years to come.