英国伦敦弗朗西斯·克里克研究所Charles Swanton团队研究了肿瘤浸润性克隆造血。2025年4月24日，《新英格兰医学杂志》发表了这一成果。

克隆性不确定潜能造血（CHIP）是一种与年龄相关的疾病，与癌症患者死亡率增加有关。具有高变异等位基因频率的CHIP突变可以在肿瘤中检测到，研究组将这种现象称为肿瘤浸润性克隆造血（TI-CH）。TI-CH的发生频率及其对肿瘤演变的影响尚不清楚。

研究组在来自TRACERx研究的421例早期非小细胞肺癌（NSCLC）患者和来自MSK-IMPACT泛癌症队列的49351例患者中鉴定了CHIP和TI-CH。还研究了TI-CH与生存和疾病复发的关系，并评估了TET2突变CHIP对肺肿瘤生物学特征的功能影响。

在非小细胞肺癌患者中，42%的CHIP患者患有TI-CH。TI-CH独立预测死亡或复发风险增加，与没有CHIP相比，调整后的风险比为1.80（95%置信区间[CI]，1.23至2.63），与没有TI-CH的CHIP相比调整后的危险比为1.62（95%CI，1.02至2.56）。H.TET2突变是TI-CH的最强遗传预测因子；这种突变增强了单核细胞向肺肿瘤细胞的迁移，促进了小鼠体内富含髓系的肿瘤微环境，并促进了肿瘤类器官的生长。

研究结果表明，TI-CH增加了非小细胞肺癌患者疾病复发或死亡的风险，以及实体瘤患者因任何原因死亡的风险。TI-CH重塑肿瘤免疫微环境，加速肿瘤类器官生长，这些发现支持衰老相关的血液学克隆增殖在癌症进化中的作用。

附：英文原文

Title: Tumor-Infiltrating Clonal Hematopoiesis

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

Issue&Volume: 2025-04-24

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.

DOI: NJ202504243921607

Source: https://www.nejm.org/doi/full/10.1056/NEJMoa2413361