Tumor-Infiltrating Clonal Hematopoiesis.
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Pich Oriol, Bernard Elsa, Zagorulya Maria, Rowan Andrew, Pospori Constandina, Slama Ramy, Huerga Encabo Hector, O'Sullivan Jennifer, Papazoglou Despoina, Anastasiou Panayiotis, Iliakis Chrysante S, Clark Sally-Ann, Dijkstra Krijn K, Barbè Vittorio, Bailey Chris, Stonestrom Aaron J, Enfield Katey S S, Green Mary, Brierley Charlotte K, Magness Alastair, Pearce David R, Hynds Robert E, Zaidi Rija, Rane Jayant K, Álvarez-Prado Ángel F, Thol Kerstin, Scott Rachel, Bola Supreet Kaur, Hoxha Elena, Harris Steve K, Peggs Karl S, Quezada Sergio A, Hackshaw Allan, Zaccaria Simone, Joyce Johanna A, Malanchi Ilaria, Berger Michael F, Jamal-Hanjani Mariam, Wack Andreas, Downward Julian, Grey William, Lo Celso Cristina, Grönroos Eva, Rudin Charles M, Mead Adam J, Bonnet Dominique, Papaemmanuil Elli, Swanton Charles
Аннотация
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.).