Age-Related Genetic Changes in Blood Linked to Poor Cancer Outcomes

Researchers from the Francis Crick Institute, UCL, Gustave Roussy, and Memorial Sloan Kettering Cancer Center (MSK) have uncovered significant insights into how age-associated genetic alterations in blood cells influence cancer progression and patient survival. The study demonstrates that the expansion of mutant blood cells, a hallmark of aging known as clonal hematopoiesis of indeterminate potential (CHIP), can infiltrate tumors and adversely affect prognosis.

CHIP involves the accumulation of mutations in blood stem cells over time, driven by natural aging and environmental factors. While previously linked to increased risks of cardiovascular diseases and other age-related disorders, its role in solid cancer development had not been fully explored.

In a comprehensive analysis published in the New England Journal of Medicine, the team examined blood samples from over 400 lung cancer patients within the TRACERx and PEACE studies, alongside data from approximately 49,000 patients with various cancers from MSK. They discovered that the presence of CHIP mutations in blood correlated with shorter overall survival, independent of age or cancer stage.

Further investigation revealed that in about 42% of patients with CHIP, these mutations were also detected within tumor tissue— a phenomenon termed tumor infiltrating clonal hematopoiesis (TI-CH). Importantly, TI-CH, rather than CHIP alone, was associated with a heightened risk of cancer relapse and mortality. Postmortem analyses of metastatic sites showed frequent presence of TI-CH mutations in tumor cells, indicating active infiltration.

The study also examined the immune landscape within tumors. Patients with TI-CH exhibited an expansion of myeloid cells, which are known to modulate inflammation and can support tumor growth. Specific mutations in the TET2 gene were linked to increased infiltration of these mutant blood cells into tumors. Laboratory experiments demonstrated that TET2-mutant myeloid cells could remodel the tumor microenvironment and promote tumor growth, suggesting a functional role in disease progression.

Expanding their scope, the researchers validated these findings across a broad range of cancers, confirming that TI-CH was a predictor of poorer survival, especially in aggressive cancers like lung, head and neck, and pancreatic cancers. The study emphasizes that age-related blood mutations can influence tumor biology and patient outcomes.

Experts highlight that understanding this interplay opens new avenues for intervention, aiming to mitigate this adverse influence of CHIP on cancer prognosis. As Dr. Oriol Pich from the Crick notes, "Blood cells carrying age-related mutations can infiltrate tumors and impact cancer evolution, leading to worse outcomes." Meanwhile, Charlie Swanton from the Crick underscores the importance of elucidating how aging-associated mutations contribute to cancer risk and progression.

This research underscores the significance of monitoring age-related blood mutations and their potential as targets for therapeutic strategies, potentially transforming approaches to cancer treatment and prevention in aging populations.