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A collaborative research effort involving the Francis Crick Institute, University College London, Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK) has revealed that the proliferation of mutant blood cells, a process linked to aging, is present in cancerous tumors and correlates with poorer patient outcomes.
Investigating the relationship between age-related genetic mutations and diseases such as cancer and cardiovascular ailments is crucial for developing preventative strategies to address the needs of an aging population.
Clonal hematopoiesis of indeterminate potential (CHIP) occurs when blood stem cells accumulate mutations due to aging and environmental influences. While previous studies have associated CHIP with increased risks for age-related conditions like cardiovascular disease, its role in the progression of solid tumors has not been extensively explored.
The findings, published in the New England Journal of Medicine, stem from analysis involving over 400 lung cancer patients participating in the Cancer Research UK-supported TRACERx and PEACE studies, alongside data from 49,000 cancer patients at MSK.
CHIP’s Influence on Cancer Prognosis
Initial assessments of blood samples enabled researchers to identify patients with CHIP mutations. When examining clinical outcomes, it became evident that these mutations were associated with reduced survival rates, independent of patient age or cancer stage at diagnosis.
Further investigation revealed that 42% of patients with CHIP also exhibited these mutations in their lung tumors, attributable to blood cell infiltration—a phenomenon termed tumor infiltrating clonal hematopoiesis (TI-CH). The study highlighted that TI-CH, rather than CHIP in isolation, was more significantly linked to increased risks of cancer recurrence and mortality.
Supporting evidence from the PEACE study focused on postmortem samples taken from metastatic sites indicated that TI-CH mutations were prevalent in tumors at these locations, underscoring their relevance in cancer progression.
Disparity Among Mutations
To investigate the association between TI-CH and adverse patient outcomes further, researchers analyzed the cellular composition of lung tumors. They discovered that patients with TI-CH exhibited a proliferation of myeloid cells, which play a notable role in the tumor microenvironment. Unlike other immune cells that combat cancer, myeloid cells have been implicated in fostering inflammation and facilitating tumor growth.
A focus on mutations in a gene known as TET2, a key regulator of blood cell production, revealed that these mutant cells were prone to infiltrate tumors. Analysis of individual tumor cells from two TI-CH patients confirmed that TET2 mutations predominantly occurred in myeloid cells as opposed to other immune variants.
Collaboration with experts in blood cancer and CHIP at the Crick, led by Dominique Bonnet, allowed the team to explore the effects of TET2 mutations experimentally. They developed mini lung tumors, or organoids, containing TET2 mutant myeloid cells, demonstrating that these cells could remodel the tumor microenvironment and enhance tumor growth.
Expanding Horizons Beyond Lung Cancer
The research team also partnered with Memorial Sloan Kettering Cancer Center researchers to validate their findings across a broader dataset encompassing over 49,000 cancer patients. The presence of TI-CH emerged as an independent predictor of reduced survival, with CHIP and TI-CH mutations varying across cancer types. Notably, these mutations were more prevalent in hard-to-treat cancers, including lung, head and neck, and pancreatic cancers.
Future research aims to establish a direct causal link between CHIP and cancer outcomes and elucidate the precise mechanisms through which CHIP contributes to the development of aggressive malignancies.
Leading the study were Oriol Pich, Elsa Bernard, and Maria Zagorulya.
Oriol Pich, a Postdoctoral Project Research Scientist in the Crick’s Cancer Evolution and Genome Instability Laboratory, commented, “Our findings indicate that blood cells harboring age-related mutations can infiltrate tumors, influencing cancer evolution and resulting in poorer patient outcomes.”
“This is significant since CHIP is a natural aspect of aging found frequently in cancer patients.”
Charlie Swanton, Deputy Clinical Director at the Crick, Chief Clinician at Cancer Research UK, and Chief Investigator for TRACERx, remarked, “This study represents a milestone in our understanding of the interplay between two forms of ‘clonal proliferation’—age-related CHIP and cancer—offering insights into the role of aging in cancer risk.”
“As we decipher the critical mutations that evolve during aging within bone marrow cells and their implications for disease, we aspire to identify potential intervention opportunities, possibly paving the way for the prevention of certain age-related cancers.”
This research was supported by Cancer Research UK as well as the National Institute of Health and Care Research UCLH Biomedical Research Centre and other contributors.
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