By Gilang Cahya 
Researchers from leading international institutions have unveiled a significant link between age-related genetic changes in blood cells and the progression of cancerous tumors, a discovery that could fundamentally alter our understanding of cancer development and treatment. The groundbreaking 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), is not only present within solid tumors but is directly associated with poorer patient prognoses across a range of cancer types. This research, a collaborative effort involving the Francis Crick Institute, UCL, Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK), sheds new light on the intricate interplay between aging, genetics, and the relentless evolution of cancer.
The Unseen Influence of Ageing: Clonal Haematopoiesis of Indeterminate Potential (CHIP)
As populations age globally, understanding the biological mechanisms that bridge age-related genetic alterations with diseases common in later life, such as cancer and cardiovascular disease, has become a critical scientific imperative. These insights are vital for developing effective preventative therapies and improving the quality of life for an increasing proportion of the world’s population.
Clonal haematopoiesis of indeterminate potential (CHIP) represents a key aspect of this age-related biological shift. It is characterized by the accumulation of specific mutations within blood stem cells over time. This process is influenced by a complex interplay of intrinsic ageing mechanisms and external environmental factors, such as exposure to carcinogens or radiation. While CHIP has been previously identified as a risk factor for age-related disorders, including cardiovascular disease and hematological malignancies, its precise role in the evolution and progression of solid tumors has remained a significant area of investigation.
The study, which leveraged data from the Cancer Research UK funded TRACERx and PEACE studies involving over 400 lung cancer patients, alongside a massive dataset of 49,000 patients with various cancers from MSK, provides the most comprehensive analysis to date of the association between CHIP and cancer. This extensive scope allows for robust statistical power, enabling researchers to draw significant conclusions about the prevalence and impact of CHIP in the oncological landscape.
CHIP in Tumors: A Marker of Aggressive Disease
The initial phase of the research involved a detailed analysis of blood samples from participating patients. By identifying the presence of CHIP mutations in their blood, the scientists were able to correlate this with clinical outcomes. The findings were stark: patients diagnosed with CHIP mutations in their blood exhibited a significantly shorter survival time, irrespective of their age at diagnosis or the stage of their cancer. This initial observation underscored the potential of CHIP as a prognostic indicator.
However, the researchers sought to delve deeper, investigating whether these blood-derived mutations were also present within the tumors themselves. They hypothesized that blood cells carrying CHIP mutations might infiltrate solid tumors, thereby influencing the tumor’s microenvironment and its growth trajectory. This phenomenon was termed "tumour infiltrating clonal haematopoiesis" (TI-CH). The study revealed that TI-CH was present in a substantial 42% of patients with CHIP. Crucially, it was TI-CH, rather than CHIP alone, that emerged as the primary driver of increased risk for cancer relapse and mortality.
This critical finding was further corroborated by data from the PEACE study, a comprehensive postmortem investigation focused on metastatic sites – the areas where cancer spreads and the leading cause of cancer-related deaths. The analysis of these metastatic tumors showed a frequent presence of TI-CH mutations, reinforcing the hypothesis that these age-related blood cell changes contribute to the dissemination and lethality of cancer.
Decoding the Mechanism: Myeloid Cells and TET2 Mutations
To unravel the precise biological mechanisms linking TI-CH to adverse patient outcomes, the research team meticulously examined the cellular composition of lung tumors. They discovered that patients exhibiting TI-CH had a notable expansion of myeloid cells within their tumors. Myeloid cells are a crucial component of the immune system and play a significant role in the tumor microenvironment. Unlike other immune cells that are programmed to detect and combat cancer, myeloid cells have been shown to modulate inflammatory responses and can actively support tumor growth and metastasis.
Further investigations focused on specific genetic mutations that are common in CHIP, particularly those affecting the TET2 gene. The TET2 gene is a critical regulator of blood cell production. The study found that when TET2 mutations were present in blood cells, these mutant cells showed a heightened propensity to infiltrate tumors. By analyzing hundreds of individual cells extracted from the tumors of two patients with TI-CH, the researchers confirmed that TET2 mutations were predominantly located within myeloid cells, rather than other immune cell types.
In a significant experimental validation, the team collaborated with experts in blood cancer and CHIP within a laboratory led by Dominique Bonnet at the Crick Institute. They successfully engineered organoids – miniature, lab-grown tumors – incorporating TET2 mutant myeloid cells. These experiments demonstrated that the presence of TET2 mutant myeloid cells profoundly altered the tumor microenvironment, leading to accelerated growth of the tumor organoids. This experimental evidence provides a direct causal link between TET2-mutated myeloid cells and enhanced tumor progression.
Broader Implications: Beyond Lung Cancer
The implications of these findings extend far beyond lung cancer. In collaboration with researchers at Memorial Sloan Kettering Cancer Center in the United States, the team analyzed a much larger and more diverse dataset encompassing over 49,000 patients with various cancer types. This validation study confirmed that the presence of TI-CH served as an independent predictor of reduced survival across the spectrum of cancers examined.
However, the prevalence of CHIP and TI-CH varied significantly depending on the cancer type. The mutations were found to be more common in cancers that are notoriously difficult to treat, including lung cancer, head and neck cancer, and pancreatic cancer. This observation suggests that TI-CH may be a particularly important factor in the aggressive behavior of these challenging malignancies.
Future Directions and Potential Interventions
The findings of this study pave the way for several critical next steps. Foremost among these is confirming the direct causal contribution of CHIP to cancer outcomes through further experimental studies. Additionally, researchers aim to meticulously detail the precise molecular mechanisms by which CHIP functionally influences the development and progression of aggressive cancers.
Oriol Pich, a Postdoctoral Project Research Scientist at the Crick and one of the study’s lead authors, emphasized the significance of the findings: "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."
Charlie Swanton, Deputy Clinical Director at the Crick and Chief Clinician at Cancer Research UK, highlighted the novelty of the research: "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." He further articulated the hope for future interventions: "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 transformative research was generously supported by Cancer Research UK and the National Institute of Health and Care Research UCLH Biomedical Research Centre, alongside other dedicated funders. The collaborative spirit and significant investment in this research underscore the global commitment to unraveling the complexities of cancer and aging, with the ultimate goal of improving patient lives. The discovery of TI-CH as a significant factor in cancer prognosis opens new avenues for diagnostic tools and therapeutic strategies, potentially offering hope for more effective treatments for patients facing these challenging diseases. The ability to identify patients with TI-CH could lead to more personalized treatment approaches, potentially involving therapies that target these infiltrating myeloid cells or mitigate their pro-tumorigenic effects.
