Arabzadeh Mona, Tang Yi-Han, Colin-Leitzinger Christelle, Marzban Sadegh, Walgenbach Daniel, Morganti Stefania, Mahaganapathy Vaidhyanathan, Harper Erika, Teng Mingxiang, Kresovich Jacob K, Washington Iman, Parsons Heather A, Garber Judy E, West Jeffrey, Ganesan Shridar, Khiabanian Hossein, Gillis Nancy
Center for Systems and Computational Biology, Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ.
Center for Biomedical Informatics, Bioinformatics Department, Rutgers Cancer Institute, Rutgers University, New Brunswick, NJ.
medRxiv. 2025 Sep 2:2025.08.27.25334581. doi: 10.1101/2025.08.27.25334581.
Clonal hematopoiesis (CH) is the age-related expansion of mutated hematopoietic stem cells without other hematologic abnormalities. In patients with solid tumors, CH is associated with higher mortality and may evolve to therapy-related myeloid neoplasms; however, the mechanisms by which cancer treatments promote CH dynamics remain largely unknown. Here, we analyzed 392 serial samples from a prospective cohort of breast cancer patients and showed that cytotoxic treatments (chemotherapy ± radiation) led to strong therapeutic bottlenecks, resulting in significant reductions in hematopoietic allelic populations and differential clonal selection. CH clones that were positively selected and expanded through dose-dependent therapeutic bottlenecks frequently harbored mutations in , , , , and . Patients with positively selected CH during treatment had the shortest progression-free and overall survival compared to patients with unchanging or negatively selected CH across all therapies. These findings, corroborated in independent breast cancer and pan-cancer cohorts, provide strong evidence for clinical relevance of changes in CH during cancer treatment which may help identify patients at high risk for inferior outcomes.
克隆性造血（CH）是指与年龄相关的突变造血干细胞的扩增，且无其他血液学异常。在实体瘤患者中，CH与较高的死亡率相关，并可能演变为治疗相关的髓系肿瘤；然而，癌症治疗促进CH动态变化的机制在很大程度上仍不清楚。在此，我们分析了来自乳腺癌患者前瞻性队列的392份连续样本，结果显示细胞毒性治疗（化疗±放疗）导致强烈的治疗瓶颈，造成造血等位基因群体显著减少和不同的克隆选择。通过剂量依赖性治疗瓶颈被阳性选择并扩增的CH克隆经常在 、 、 、 和 中携带突变。与在所有治疗中CH无变化或被阴性选择的患者相比，治疗期间CH被阳性选择的患者无进展生存期和总生存期最短。这些发现在独立的乳腺癌和泛癌队列中得到证实，为癌症治疗期间CH变化的临床相关性提供了有力证据，这可能有助于识别预后较差的高危患者。
