Genetic Changes Linked to Aging Found to Influence Cancer Outcomes

Recent research conducted by a collaboration of scientists from the Francis Crick Institute, University College London, Gustave Roussy, and Memorial Sloan Kettering Cancer Center has unveiled critical connections between aging-related genetic alterations in blood cells and the prognosis of cancer patients. The study highlights that the proliferation of mutated blood cells, known as clonal hematopoiesis of indeterminate potential (CHIP), is not only prevalent among older adults but is also linked to poorer cancer outcomes.

CHIP occurs when blood stem cells accumulate mutations due to aging and environmental factors. While prior studies have established a correlation between CHIP and age-associated disorders, such as cardiovascular diseases, its role in cancer progression has been less explored. The findings of this research, published in the New England Journal of Medicine, reveal how CHIP affects cancer evolution, particularly in solid tumors.

The extensive analysis involved over 400 lung cancer patients from the TRACERx and PEACE studies, alongside a larger cohort of 49,000 cancer patients from MSK. Initial blood sample examinations allowed researchers to identify patients with CHIP mutations, which correlated with shorter survival rates regardless of age or cancer stage.

Upon further examination, researchers noted that 42% of patients with CHIP exhibited the presence of these mutations in their lung tumors, describing this occurrence as tumor-infiltrating clonal hematopoiesis (TI-CH). This phenomenon, rather than CHIP alone, was found to significantly correlate with increased risks of cancer relapse and mortality.

Support for these findings came from postmortem analyses in the PEACE study, which identified TI-CH mutations in metastatic tumors, signifying their role in cancer progression and mortality.

Delving deeper into the mechanisms, the research team focused on the composition of immune cells within lung tumors. They discovered that patients with TI-CH had a notable increase in myeloid cells, a type of immune cell typically associated with inflammation and tumor support, rather than direct cancer combat.

Furthermore, the study identified that mutations in the TET2 gene, a crucial regulator for blood cell production, were frequently found in myeloid cells infiltrating tumors. Experimental work with miniaturized lung tumor organoids demonstrated that TET2 mutant myeloid cells not only altered the tumor environment but also accelerated tumor growth.

The collaborative effort extended to validating these findings across various cancer types, confirming that TI-CH stands as an independent predictor of reduced survival rates. Interestingly, the prevalence of CHIP and TI-CH mutations varied among cancer types, with higher occurrences noted in more aggressive cancers such as lung, head and neck, and pancreatic cancers.

In conclusion, this investigation marks a significant advancement in understanding how age-related genetic factors can influence cancer prognosis. The researchers aim to further explore the direct contributions of CHIP to cancer outcomes and elucidate the mechanisms by which it fosters the development of aggressive cancer forms.