By Billy Candra 
The groundbreaking research, published today in the prestigious New England Journal of Medicine, sheds critical light on the complex interplay between the natural process of ageing, age-related genetic changes, and the progression of solid cancers. This discovery identifies a previously underappreciated mechanism by which age-acquired mutations in blood stem cells, a condition known as clonal haematopoiesis of indeterminate potential (CHIP), can significantly influence the trajectory of cancer and impact patient survival. The findings underscore the urgent need for a deeper understanding of the biological interface connecting age-related genetic alterations and diseases of ageing, such as cancer and cardiovascular disease, to pave the way for novel preventative and therapeutic strategies for an increasingly older global population.
Unveiling the Age-Cancer Nexus
Clonal haematopoiesis of indeterminate potential (CHIP) is a condition characterized by the accumulation of somatic mutations in blood stem cells over time. This phenomenon is largely influenced by the ageing process itself, alongside various external environmental factors like smoking or exposure to certain toxins. As individuals age, their blood stem cells can acquire mutations, leading to the clonal expansion of these mutated cells, which then contribute disproportionately to the production of new blood cells. While CHIP is common in older adults, affecting approximately 10-15% of individuals over 65, it has long been recognized as a risk factor for various age-related disorders, including cardiovascular disease, stroke, and inflammatory conditions. However, its direct impact on the evolution and prognosis of solid cancers – cancers that form solid tumours, as opposed to liquid cancers like leukaemia – had not been thoroughly investigated until now.
This new study, a collaborative effort across leading research institutions including the Francis Crick Institute, University College London (UCL), Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK), provides the most detailed examination to date of the link between CHIP and cancer outcomes. The researchers embarked on an extensive analysis involving over 400 patients with lung cancer, drawing data from the Cancer Research UK-funded TRACERx and PEACE studies, and further validated their findings using a vast dataset of 49,000 patients with various cancer types from MSK. This multi-cohort approach ensured robust validation and broad applicability of their discoveries.
A Multi-Stage Investigation: From Blood to Tumour
The research journey commenced with an initial examination of blood samples collected from the lung cancer patient cohorts. This screening allowed the scientific team to identify which patients harboured CHIP mutations in their circulating blood cells. By meticulously matching these genetic profiles with comprehensive clinical data, a striking correlation emerged: patients with CHIP mutations exhibited a statistically significant association with shorter overall survival. Crucially, this association remained consistent and independent of other established prognostic factors, such as the patient’s age at diagnosis or the stage at which their cancer was identified. This initial observation served as a compelling impetus for the researchers to delve deeper into the precise mechanisms at play.
The next critical phase involved a more granular investigation into patients diagnosed with CHIP. The team sought to determine whether these specific age-related blood cell mutations were not only present in the bloodstream but had also infiltrated the actual lung tumours. This phenomenon, where CHIP-mutated blood cells penetrate the tumour microenvironment, was indeed observed in a substantial proportion of patients – 42% of those with CHIP. The researchers coined a new term for this specific infiltration: Tumour Infiltrating Clonal Haematopoiesis (TI-CH). Their subsequent analysis yielded a pivotal insight: it was the presence of TI-CH, rather than CHIP alone in the blood, that was strongly associated with a significantly greater risk of cancer relapse and, tragically, cancer-related mortality. This distinction highlights the localized interaction within the tumour as a critical determinant of prognosis.
Further corroboration for this finding came from samples generously provided by the PEACE study, a unique post-mortem investigation designed to map the spread of cancer, particularly in metastatic sites – the primary cause of cancer death. The team’s analysis of these metastatic tumours frequently revealed the presence of TI-CH mutations, reinforcing the notion that these infiltrating cells play a detrimental role in advanced, aggressive disease.
Decoding Cellular Mechanisms: Myeloid Cells and TET2 Mutations
To unravel the underlying biological link between TI-CH and adverse patient outcomes, the scientists meticulously scrutinized the cellular composition within the lung tumours. Their investigations uncovered a consistent pattern: patients with TI-CH exhibited an abnormal expansion of myeloid cells, a specific type of immune cell. The tumour microenvironment, a complex ecosystem surrounding the cancer cells, is known to be heavily influenced by various immune cell populations. While some immune cells, such as cytotoxic T lymphocytes, are crucial for recognizing and eliminating cancer cells, myeloid cells often play a more nuanced and sometimes detrimental role. Previous research has shown that myeloid cells can modulate inflammation, suppress anti-tumour immune responses, promote angiogenesis (new blood vessel formation to feed the tumour), and even directly support tumour progression and metastasis. Their increased presence in TI-CH tumours suggested a pro-tumourigenic shift in the immune landscape.
The researchers also made a significant discovery regarding specific genetic mutations. They found that when mutations affected a gene named TET2, which is a vital regulator of blood cell production and differentiation, these TET2 mutant blood cells were notably more prone to infiltrating tumours across thousands of individuals studied. TET2 plays a crucial role in epigenetic regulation, influencing gene expression without altering the underlying DNA sequence, and its disruption can lead to abnormal haematopoietic stem cell function. To pinpoint the exact cellular location of these mutations, the team conducted single-cell sequencing on hundreds of cells isolated from the tumours of two patients with TI-CH. This high-resolution analysis confirmed that TET2 mutations were predominantly present within the myeloid cell population, conspicuously absent from other immune cell types within the tumour. This specificity further solidified the link between TET2 mutated myeloid cells and the observed adverse outcomes.
To experimentally validate these observations, the research team collaborated with renowned experts in blood cancer and CHIP at a Crick laboratory led by Dominique Bonnet. Together, they designed elegant experiments using organoids – three-dimensional mini lung tumours grown in a laboratory setting. They introduced TET2 mutant myeloid cells into these organoid cultures. The results were compelling: the TET2 mutant myeloid cells actively remodelled the tumour microenvironment, creating conditions conducive to accelerated tumour organoid growth. This direct experimental evidence provided strong causal support for the hypothesis that TET2-mutated myeloid cells, originating from CHIP, actively contribute to tumour aggression.
Broader Implications and Validation Across Cancers
A pivotal aspect of this study involved validating the findings on a much larger scale and across a diverse array of cancer types. Collaborating with researchers at the Memorial Sloan Kettering Cancer Center (MSK) in the US, the team leveraged an extensive dataset comprising over 49,000 patients diagnosed with various forms of cancer. This large-scale validation confirmed that, overall, the presence of TI-CH served as an independent and robust predictor of shorter survival across this broad spectrum of malignancies.
However, the prevalence of both CHIP and TI-CH varied significantly among different cancer types. The researchers observed that these age-related mutations were notably more common in cancers that are notoriously harder to treat and often carry a poorer prognosis. This included aggressive forms such as lung cancer, head and neck cancer, and pancreatic cancer – diseases where therapeutic options are often limited and patient outcomes remain challenging. This differential distribution suggests that the interplay between CHIP/TI-CH and tumour biology might be cancer-type specific, potentially offering clues for tailored diagnostic and therapeutic approaches.
Future Directions and Therapeutic Potential
The immediate next steps for this transformative research involve confirming the direct causal contribution of CHIP to cancer outcomes through additional functional studies. Researchers are keen to detail the precise molecular and cellular mechanisms by which CHIP, and specifically TI-CH, is functionally implicated in the development and progression of aggressive cancers. This includes investigating the specific signalling pathways activated by TET2 mutant myeloid cells and their exact interactions with cancer cells and other components of the tumour microenvironment.
Oriol Pich, a Postdoctoral Project Research Scientist in the Crick’s Cancer Evolution and Genome Instability Laboratory and a lead author of the study, emphasized the significance of these 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, suggesting a widespread but previously unrecognized vulnerability."
Charlie Swanton, Deputy Clinical Director at the Crick, Chief Clinician at Cancer Research UK, and Chief Investigator for the TRACERx study, highlighted the broader implications for understanding cancer in an ageing population. "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 explained. "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 insights garnered from this study open several promising avenues for clinical translation. Firstly, the identification of TI-CH as a strong prognostic marker suggests the potential for new diagnostic tools. Screening cancer patients for CHIP and subsequently for TI-CH could help stratify patients into different risk groups, allowing for more personalized treatment strategies, potentially including more intensive therapies for those with TI-CH. Secondly, understanding the specific role of TET2 mutations and myeloid cells offers novel therapeutic targets. Developing drugs that modulate the function of TET2-mutated myeloid cells or alter the pro-tumourigenic tumour microenvironment they create could represent a new frontier in cancer treatment.
Furthermore, given the prevalence of CHIP in the ageing population, this research also raises questions about preventative strategies. If CHIP directly contributes to cancer aggressiveness, future research might explore whether interventions aimed at mitigating the expansion of CHIP clones or their infiltration into tumours could reduce cancer risk or improve outcomes in older individuals. This work was generously supported by Cancer Research UK and the National Institute of Health and Care Research UCLH Biomedical Research Centre, alongside additional funders, underscoring the collaborative spirit and significant investment required for such impactful scientific endeavours. The discovery represents a major step forward in understanding how the biology of ageing intersects with cancer, offering hope for new strategies to combat this devastating disease in an increasingly elderly global population.
