Clonal hematopoiesis (CH) driven by mutations in the DNA damage response (DDR) pathway is frequent in patients with cancer and is associated with a higher risk of therapy-related myeloid neoplasms (t-MNs). Here, we analyzed 423 serial whole blood and plasma samples from 103 patients with relapsed high-grade ovarian cancer receiving carboplatin, poly(ADP-ribose) polymerase inhibitor (PARPi) and heat shock protein 90 inhibitor (HSP90i) treatment within the phase II EUDARIO trial using error-corrected sequencing of 72 genes. DDR-driven CH was detected in 35% of patients and was associated with longer duration of prior PARPi treatment. TP53- and PPM1D-mutated clones exhibited substantially higher clonal expansion rates than DNMT3A- or TET2-mutated clones during treatment. Expansion of DDR clones correlated with HSP90i exposure across the three study arms and was partially abrogated by the presence of germline mutations related to homologous recombination deficiency. Single-cell DNA sequencing of selected samples revealed clonal exclusivity of DDR mutations, and identified DDR-mutated clones as the origin of t-MN in two investigated cases. Together, these results provide unique insights into the architecture and the preferential selection of DDR-mutated hematopoietic clones under intense DNA-damaging treatment. Specifically, PARPi and HSP90i therapies pose an independent risk for the expansion of DDR-CH in a dose-dependent manner.

由 DNA 损伤反应 (DDR) 通路突变驱动的克隆造血 (CH) 在癌症患者中很常见，并且与治疗相关的骨髓肿瘤 (t-MN) 的较高风险相关。在此，我们分析了来自 103 名复发性高级别卵巢癌患者的 423 个连续全血和血浆样本，这些患者在 II 期 EUDARIO 中接受卡铂、聚（ADP-核糖）聚合酶抑制剂 (PARPi) 和热休克蛋白 90 抑制剂 (HSP90i) 治疗使用 72 个基因的纠错测序进行试验。 35% 的患者检测到 DDR 驱动的 CH，并且与先前 PARPi 治疗持续时间较长有关。TP53和PPM1D突变克隆在治疗期间表现出比DNMT3A或TET2突变克隆高得多的克隆扩增率。 DDR 克隆的扩展与三个研究组中 HSP90i 的暴露相关，并且由于与同源重组缺陷相关的种系突变的存在而被部分消除。对选定样本的单细胞 DNA 测序揭示了 DDR 突变的克隆排他性，并在两个研究案例中确定了 DDR 突变克隆是 t-MN 的起源。总之，这些结果提供了对 DDR 突变造血克隆在强烈 DNA 损伤处理下的结构和优先选择的独特见解。具体而言，PARPi 和 HSP90i 疗法以剂量依赖性方式对 DDR-CH 的扩张构成独立风险。