Tumor-Infiltrating Clonal Hematopoiesis

Journal article

BackgroundClonal hematopoiesis of indeterminate potential (CHIP) is an age-related condition associated with increased mortality among patients with cancer. CHIP mutations with high variant-allele frequencies can be detected in tumors, a phenomenon we term tumor-infiltrating clonal hematopoiesis (TI-CH). The frequency of TI-CH and its effect on tumor evolution are unclear.MethodsWe characterized CHIP and TI-CH in 421 patients with early-stage non-small-cell lung cancer (NSCLC) from the TRACERx study and in 49,351 patients from the MSK-IMPACT pan-cancer cohort. We studied the association of TI-CH with survival and disease recurrence and evaluated the functional effect of TET2-mutant CHIP on the biologic features of lung tumors.ResultsAmong patients with NSCLC, 42% of those with CHIP had TI-CH. TI-CH independently predicted an increased risk of death or recurrence, with an adjusted hazard ratio of 1.80 (95% confidence interval [CI], 1.23 to 2.63) as compared with the absence of CHIP and an adjusted hazard ratio of 1.62 (95% CI, 1.02 to 2.56) as compared with CHIP in the absence of TI-CH. Among patients with solid tumors, 26% of those with CHIP had TI-CH. TI-CH conferred a risk of death from any cause that was 1.17 times (95% CI, 1.06 to 1.29) as high as the risk with CHIP in the absence of TI-CH. TET2 mutations were the strongest genetic predictor of TI-CH; such mutations enhanced monocyte migration to lung tumor cells, fueled a myeloid-rich tumor microenvironment in mice, and resulted in the promotion of tumor organoid growth.ConclusionsTI-CH increased the risk of disease recurrence or death among patients with NSCLC and the risk of death from any cause among patients with solid tumors. TI-CH remodeled the tumor immune microenvironment and accelerated tumor organoid growth, findings that support a role for an aging-related hematologic clonal proliferation in cancer evolution. (Funded by the Royal Society and others.).

Authors: Pich, O; Bernard, E; Zagorulya, M; Rowan, A; Pospori, C

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Massachusetts Medical Society
• Journal: New England Journal of Medicine
• Volume: 392
• Issue: 16
• Pages: 1594-1608
• Publication date: 2025-04-01
• DOI: 10.1056/nejmoa2413361
• EISSN: 1533-4406
• ISSN: 0028-4793
• Pmid: 40267425
• Language: English
• Keywords: Animals; Mutation; Observational Studies as Topic; Lung Neoplasms; Neoplasm Recurrence, Local; Monocytes; Neoplasm Transplantation; Humans; Prospective Studies; Dioxygenases; Female; Aged; Middle Aged; Male; DNA-Binding Proteins; Mice; Clonal Hematopoiesis; Cell Line, Tumor; Carcinoma, Non-Small-Cell Lung; Cell Movement; Tumor Microenvironment