By Gilang Cahya 
Researchers from leading institutions, including the Francis Crick Institute, University College London (UCL), Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK), have unveiled a significant discovery linking age-related genetic changes in blood cells to more aggressive cancer progression and poorer patient prognoses. The study, published in the prestigious New England Journal of Medicine, identifies the presence of "clonal haematopoiesis of indeterminate potential" (CHIP) mutations within solid tumors, a phenomenon previously associated with aging and increased risk of cardiovascular disease, but whose impact on cancer evolution remained largely unexplored. This groundbreaking research suggests that the aging process itself, through alterations in blood stem cells, may actively contribute to the aggressiveness of certain cancers.
Understanding Clonal Haematopoiesis of Indeterminate Potential (CHIP)
Clonal haematopoiesis of indeterminate potential (CHIP) is a condition characterized by the accumulation of specific genetic mutations in blood stem cells. These mutations arise as a natural consequence of aging, influenced by both intrinsic cellular processes and external environmental factors such as exposure to toxins or radiation. While CHIP has been recognized for some time as a risk factor for age-related diseases, including cardiovascular conditions like heart attacks and strokes, its direct role in the development and progression of solid tumors has been a subject of intense scientific inquiry. The current study represents a major leap forward in understanding this complex biological interplay.
The research leveraged data from two large-scale studies: the Cancer Research UK-funded TRACERx and PEACE studies, which meticulously analyzed over 400 patients with lung cancer, and an extensive dataset comprising 49,000 patients with various cancer types from MSK. This comprehensive approach allowed the scientists to not only identify the presence of CHIP mutations but also to investigate their localization and impact within the tumor microenvironment.
The Discovery: CHIP Mutations Infiltrate Tumors, Signaling Worse Prognosis
The initial phase of the research involved analyzing blood samples from patients to identify those with CHIP mutations. The findings were stark: patients with CHIP exhibited a significantly shorter lifespan, irrespective of their age at diagnosis or the stage of their cancer. This correlation underscored the potential of these age-related blood cell alterations to influence cancer outcomes.
However, the researchers delved deeper, seeking to determine if these CHIP mutations were also present within the solid tumors themselves, suggesting an infiltration of these mutated blood cells. This phenomenon, termed "tumour infiltrating clonal haematopoiesis" (TI-CH), was observed in a substantial 42% of patients with CHIP. Crucially, it was TI-CH, rather than CHIP alone, that emerged as the strong predictor of increased risk for cancer relapse and cancer-specific mortality.
This critical finding was further corroborated by data from the PEACE study, a postmortem investigation focused on metastatic sites – the areas where cancer spreads and the primary cause of cancer-related deaths. The analysis of metastatic tumors from these sites revealed a frequent presence of TI-CH mutations, reinforcing the association between these infiltrating blood cells and the spread of cancer.
Delving into the Mechanism: Myeloid Cells and the TET2 Gene
To unravel the biological underpinnings of this association between TI-CH and poor patient outcomes, the scientists meticulously examined the cellular composition of lung tumors. They discovered that patients with TI-CH displayed an expansion of myeloid cells, a specific type of immune cell. Myeloid cells play a complex role within the tumor microenvironment. Unlike some immune cells that are programmed to identify and combat cancer, myeloid cells are known to modulate inflammation and can, in certain contexts, actively support tumor growth and dissemination.
Further investigation revealed a specific genetic culprit: mutations in the TET2 gene. The TET2 gene is a crucial regulator of blood cell production. The study found that when TET2 mutations were present in blood cells, these mutant cells were more likely to infiltrate tumors. Analysis of hundreds of individual cells from the tumors of patients with TI-CH confirmed that TET2 mutations were predominantly found in myeloid cells, but not in other types of immune cells, highlighting a specific pathway of infiltration.
In a significant experimental validation, researchers collaborated with blood cancer and CHIP experts at the Crick Institute, led by Dominique Bonnet. They successfully grew organoids – miniature tumors in a lab setting – incorporating TET2-mutant myeloid cells. This experiment demonstrated that TET2-mutant myeloid cells could actively remodel the tumor microenvironment and accelerate the growth of these tumor organoids. This provides direct evidence that these age-related blood cell mutations can have a direct, pro-tumorigenic effect.
Broader Implications Across Cancer Types
The reach of this discovery extends beyond lung cancer. In collaboration with researchers at Memorial Sloan Kettering Cancer Center, the team analyzed a massive dataset of over 49,000 patients with a diverse range of cancers. This larger cohort confirmed that the presence of TI-CH was an independent predictor of reduced survival across various cancer types.
The study also revealed variations in the prevalence of CHIP and TI-CH across different cancers. These 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 the interplay between aging and cancer may be particularly pronounced in these aggressive malignancies.
Future Directions and Potential for Intervention
The implications of this research are far-reaching, opening new avenues for understanding cancer development and potentially leading to novel therapeutic strategies. The immediate next steps for the research team include confirming that CHIP directly contributes to cancer outcomes and further detailing the precise mechanisms by which CHIP functionally influences the development of aggressive cancers.
Dr. Oriol Pich, a lead researcher on the project and Postdoctoral Project Research Scientist at the Crick’s Cancer Evolution and Genome Instability Laboratory, stated, "Our results show that blood cells carrying age-related mutations can infiltrate tumors and impact cancer evolution, leading to worse outcomes for patients. This is important because CHIP is a natural phenomenon of ageing that is common in patients with cancer."
Professor Charlie Swanton, Deputy Clinical Director at the Crick and Chief Clinician at Cancer Research UK, who is also the Chief Investigator for the TRACERx study, emphasized the significance of the findings: "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. 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."
This pioneering work was generously supported by Cancer Research UK and the National Institute of Health and Care Research UCLH Biomedical Research Centre, alongside other dedicated funders, underscoring the collaborative and well-supported nature of this critical scientific endeavor. The findings offer a glimmer of hope for developing new strategies to combat age-related cancers by targeting the influence of aging processes on tumor development.
