By Gilang Cahya 
Researchers from a consortium of leading institutions, including the Francis Crick Institute, University College London (UCL), Gustave Roussy in France, and Memorial Sloan Kettering Cancer Center (MSK) in the United States, have unveiled a significant discovery linking age-related genetic changes in blood cells to poorer prognoses in cancer patients. Their 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), can infiltrate solid tumours and is directly associated with a higher risk of cancer relapse and mortality. This finding has profound implications for understanding the interplay between ageing, genetic mutations, and cancer progression, particularly as global populations age.
Unraveling the Link: CHIP and Cancer Evolution
The research addresses a critical gap in understanding the biological interface between age-related genetic alterations and diseases of ageing, such as cancer and cardiovascular disease. CHIP, characterized by the accumulation of mutations in blood stem cells over time, is influenced by both the natural ageing process and external environmental factors. While CHIP has previously been identified as a risk factor for age-related disorders like cardiovascular disease, its direct impact on the evolution and progression of solid cancers remained largely uninvestigated until this comprehensive study.
The study meticulously examined over 400 patients with lung cancer enrolled in the Cancer Research UK-funded TRACERx and PEACE studies. This was complemented by an extensive analysis of data from approximately 49,000 patients with various cancer types at MSK. The initial phase involved analysing blood samples to identify patients with CHIP mutations. When correlated with clinical data, a stark association emerged: patients with CHIP mutations were found to have significantly shorter survival times, irrespective of their age or the stage at which their cancer was diagnosed.
Tumour Infiltrating Clonal Haematopoiesis (TI-CH): A New Biomarker for Poor Prognosis
Further investigation delved deeper into the presence of these CHIP mutations within the solid tumours themselves. The research team sought to determine if the genetic changes observed in the blood were also present in lung tumours due to the infiltration of these mutant blood cells. This phenomenon, termed Tumour Infiltrating Clonal Haematopoiesis (TI-CH), was identified in a substantial 42% of patients diagnosed with CHIP. Crucially, the study found that it was TI-CH, rather than CHIP alone, that correlated with a markedly increased risk of cancer relapse and death.
This critical observation was further substantiated by data from the PEACE study, a post-mortem investigation focusing on metastatic sites – the areas where cancer spreads and which are the primary cause of cancer-related deaths. The analysis of these metastatic tumours revealed that TI-CH mutations were frequently present in these advanced disease sites, reinforcing the link between infiltrating mutant blood cells and aggressive cancer spread.
Deconstructing the Mechanism: Myeloid Cells and TET2 Mutations
To elucidate the mechanisms underlying the association between TI-CH and poor patient outcomes, the scientists scrutinized the cellular composition of lung tumours. They observed that patients with TI-CH exhibited an expansion of myeloid cells, a specific type of immune cell. Myeloid cells play a crucial role in the tumour microenvironment. Unlike certain immune cells that are programmed to detect and eliminate cancer cells, myeloid cells are known to regulate inflammation and can, under certain circumstances, promote tumour growth and metastasis.
The researchers also pinpointed the significance of mutations in the TET2 gene, a critical regulator of blood cell production. Their analysis across thousands of individuals indicated that blood cells carrying TET2 mutations were more prone to infiltrate tumours. Through detailed single-cell analysis of tumour samples from two patients with TI-CH, they confirmed that TET2 mutations were predominantly found within myeloid cells, and notably absent in other immune cell populations.
In a crucial experimental validation, the research team collaborated with blood cancer and CHIP experts at the Crick Institute, led by Dominique Bonnet. They successfully generated organoids, essentially miniature lung tumours, in the laboratory. When these organoids were co-cultured with TET2-mutant myeloid cells, the study demonstrated that these mutant myeloid cells actively remodelled the tumour microenvironment and significantly accelerated the growth of the tumour organoids. This experimental evidence provides a direct causal link between TET2-mutant myeloid cell infiltration and enhanced tumour progression.
Broadening the Scope: Implications Across Cancer Types
The study’s impact was further amplified by its validation across a much larger and diverse patient cohort. Collaborating with researchers at Memorial Sloan Kettering Cancer Center, the team analysed data from over 49,000 patients with a wide array of cancer types. This extensive dataset confirmed that the presence of TI-CH served as an independent predictor of shorter survival across different malignancies.
However, the prevalence of CHIP and TI-CH varied significantly depending on the specific cancer type. The mutations were found to be more common in cancers known for their challenging treatment and poorer prognoses, including lung cancer, head and neck cancer, and pancreatic cancer. This observation suggests that the interplay between ageing-related blood cell mutations and cancer may be a more pervasive driver of aggressive disease than previously understood.
Future Directions and Potential Interventions
The implications of this research are far-reaching, opening new avenues for diagnostic tools and therapeutic strategies. The next critical steps for the research team involve confirming the direct causal contribution of CHIP to cancer outcomes and meticulously detailing the precise mechanisms by which CHIP functionally influences the development 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 demonstrate that blood cells carrying age-related mutations can infiltrate tumours and alter cancer evolution, leading to worse outcomes for patients. This is particularly important because CHIP is a common, natural phenomenon of ageing observed in many cancer patients."
Charlie Swanton, Deputy Clinical Director at the Crick and Chief Clinician at Cancer Research UK, highlighted the novelty of the work: "This study marks the first time we have been able to observe at scale the interaction between two distinct types of ‘clonal proliferations’ – age-related CHIP and cancer. This provides invaluable insight into how ageing itself might contribute to cancer risk." He further expressed optimism about future developments: "As we begin to piece together the puzzle of the most critical mutations that arise during the ageing process within bone marrow cells, and their impact on disease, we hope to identify opportunities for intervention and potentially even the prevention of certain age-related cancers."
This extensive research was generously supported by Cancer Research UK and the National Institute of Health and Care Research UCLH Biomedical Research Centre, alongside contributions from other dedicated funders. The collaborative nature of the study, spanning multiple institutions and involving a large number of patients, underscores the global effort to unravel complex biological processes and translate these discoveries into tangible benefits for patients. The identification of TI-CH as a prognostic marker could lead to more personalized risk stratification for cancer patients, enabling clinicians to tailor treatment strategies based on the presence and nature of these age-related genetic infiltrations. Furthermore, understanding the specific role of mutant myeloid cells could pave the way for novel therapeutic approaches aimed at targeting or modifying these cells within the tumour microenvironment, potentially offering new hope for patients with aggressive or treatment-resistant cancers.
