Tumor-infiltrating clonal hematopoiesis Journal Article
| Authors: | Pich, O.; Bernard, E.; Zagorulya, M.; Rowan, A.; Pospori, C.; Slama, R.; Huerga Encabo, H.; O'Sullivan, J.; Papazoglou, D.; Anastasiou, P.; Iliakis, C. S.; Clark, S. A.; Dijkstra, K. K.; Barbè, V.; Bailey, C.; Stonestrom, A. J.; Enfield, K. S. S.; Green, M.; Brierley, C. K.; Magness, A.; Pearce, D. R.; Hynds, R. E.; Zaidi, R.; Rane, J. K.; Álvarez-Prado, ÁF; Thol, K.; Scott, R.; Bola, S. K.; Hoxha, E.; Harris, S. K.; Peggs, K. S.; Quezada, S. A.; Hackshaw, A.; Zaccaria, S.; Joyce, J. A.; Malanchi, I.; Berger, M. F.; Jamal-Hanjani, M.; Wack, A.; Downward, J.; Grey, W.; Lo Celso, C.; Grönroos, E.; Rudin, C. M.; Mead, A. J.; Bonnet, D.; Papaemmanuil, E.; Swanton, C. |
| Article Title: | Tumor-infiltrating clonal hematopoiesis |
| Abstract: | BACKGROUND: Clonal 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. METHODS: We 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. RESULTS: Among 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. CONCLUSIONS: TI-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.). Copyright © 2025 Massachusetts Medical Society. |
| Keywords: | aged; middle aged; dna binding protein; tet2 protein, human; genetics; mutation; dna-binding proteins; proto-oncogene proteins; mortality; mouse; animal; animals; mice; neoplasm recurrence, local; carcinoma, non-small-cell lung; lung neoplasms; pathology; lung tumor; tumor recurrence; non small cell lung cancer; clonal hematopoiesis; dioxygenase; humans; human; male; female; proto oncogene protein; dioxygenases |
| Journal Title: | New England Journal of Medicine |
| Volume: | 392 |
| Issue: | 16 |
| ISSN: | 0028-4793 |
| Publisher: | Massachusetts Medical Society |
| Date Published: | 2025-04-01 |
| Start Page: | 1594 |
| End Page: | 1608 |
| Language: | English |
| DOI: | 10.1056/NEJMoa2413361 |
| PUBMED: | 40267425 |
| PROVIDER: | scopus |
| PMCID: | PMC12021423 |
| DOI/URL: | |
| Notes: | Source: Scopus |
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