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Clonal hematopoiesis of indeterminate potential (CHIP) found in tumors (TI-CH) increases cancer recurrence and mortality risk. This age-related condition impacts tumor microenvironment and growth, highlighting its role in cancer evolution.

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Area of Science:

  • Oncology
  • Hematology
  • Genetics

Background:

  • Clonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition linked to higher cancer mortality.
  • CHIP mutations can infiltrate tumors, forming tumor-infiltrating CH (TI-CH), but its prevalence and impact are not well understood.

Purpose of the Study:

  • To determine the frequency of TI-CH in early-stage non-small-cell lung cancer (NSCLC) and a pan-cancer cohort.
  • To investigate the association of TI-CH with patient survival and disease recurrence.
  • To evaluate the functional impact of TET2-mutant CHIP on lung tumor biology.

Main Methods:

  • Characterized CHIP and TI-CH in 421 early-stage NSCLC patients (TRACERx study) and 49,351 patients (MSK-IMPACT cohort).
  • Analyzed the association between TI-CH and survival/recurrence outcomes.
  • Assessed the functional effects of TET2 mutations in CHIP on lung tumor features.

Main Results:

  • TI-CH was present in 42% of CHIP patients with NSCLC and 26% of CHIP patients with solid tumors.
  • TI-CH independently predicted increased risk of death or recurrence in NSCLC and increased all-cause mortality in solid tumors.
  • TET2 mutations, the strongest predictor of TI-CH, promoted monocyte migration, fueled myeloid-rich tumor microenvironments in mice, and enhanced tumor organoid growth.

Conclusions:

  • TI-CH significantly increases the risk of disease recurrence or death in NSCLC and solid tumors.
  • TI-CH alters the tumor immune microenvironment and accelerates tumor growth, suggesting a role in cancer evolution.
  • Aging-related clonal hematopoiesis contributes to cancer progression.