Impact of Oncologic Therapy on Clonal Hematopoiesis and Subsequent Risk of Therapy-Related Leukemia

摘要 大多数原发性肿瘤类型的癌症幸存者发生继发性骨髓肿瘤的风险增加 (tMN)一种高度致命的疾病。然而，这种关联的机制和患者人群 足够高的风险，以保证干预是不完善的。克隆性造血（CH）是一种前 白血病状态，使tMN的风险大大增加。我们已经建立了一个包含17500个 已接受靶向血液测序并具有相关综合临床注释的患者。 该队列的初步数据显示，暴露于特定的肿瘤治疗与CH相关。 显示tMN高风险患者的亚群可以基于CH突变和临床 特色我们的中心假设是CH可用于预测tMN风险，并且这种“高风险”CH 通过暴露于特定的肿瘤治疗来促进。首先，我们建议描述先前暴露如何 特异性肿瘤治疗与CH和克隆扩增的存在有关。我们将在25000年研究这个问题， 通过常规临床分子谱检查检测CH的实体瘤患者。我们将比较 既往接受过治疗（60%）和未接受过治疗（40%）的实体瘤患者的CH突变特征。 其次，我们将明确与实体瘤中髓样肿瘤相关的分子和临床特征 患者这将通过对tMN病例和从生物库中选择的匹配对照进行测序来实现。 实体瘤患者的血液样品。我们假设，考虑CH分子特征， 结合临床因素和治疗暴露可预测髓系肿瘤的发生 癌症患者的发展。这将导致一个风险预测模型的发展t-MN 实体瘤患者的发展。第三，我们将确定患者获得CH突变的时间 接受高风险的治疗。我们假设接受高风险治疗 驱动治疗前血液样品中低水平存在的预先存在的CH克隆的克隆扩增。到 为实现这一目标，将前瞻性采集治疗前、治疗中和治疗后血样， 进行。我们的研究提案旨在提供一个统计动力和基于证据的资源 这将使我们能够详细了解CH、治疗暴露和随后的 TMN风险。我们的研究结果将有助于发展基于基因组的实体瘤tMN风险评估 患者这将指导不同原发部位实体瘤患者的合理治疗决策 旨在最大限度地减少tMN风险，这是长期生存的主要障碍。

ABSTRACT Cancer survivors across most primary tumor types are at a heightened risk for secondary myeloid neoplasms (tMN), a highly lethal disease. However, the mechanism underlying this association and the patient populations at adequately high risk to warrant intervention are not well-established. Clonal hematopoiesis (CH) is a pre- leukemic state that confers a substantially increased risk of tMN. We have developed a database of 17,500 patients who have undergone targeted blood sequencing with associated comprehensive clinical annotation. Preliminary data from this cohort shows that exposure to specific oncologic therapies is associated with CH. We show that subsets of patients at high risk of tMN can be defined based on CH mutational and clinical characteristics. Our central hypothesis is that CH can be used to predict tMN risk and that this “high-risk” CH is promoted by exposure to specific oncologic therapies. First, we propose to characterize how prior exposure specific oncologic therapies is related to the presence of CH and clonal expansion. We will study this in 25,000 solid tumor patients who were tested for CH through routine clinical molecular profiling workup. We will compare CH mutational characteristics among previously treated (60%) and untreated (40%) solid tumor patients. Second, we will define the molecular and clinical features associated with myeloid neoplasm in solid tumor patients. This will be achieved though sequencing of tMN cases and matched controls selected from bio-banked blood samples of solid tumor patients. We hypothesize that consideration of CH molecular features in combination with clinical factors and treatment exposures predict development of myeloid neoplasm development in cancer patients. This will result in the development of a risk-prediction model for t-MN development in solid tumor patients. Third, we will define the timing of CH mutation acquisition in patients receiving high-risk therapy through serial mutational profiling. We hypothesize that exposure to high-risk therapy drives clonal expansion of pre-existing CH clones present in low levels in pre-treatment blood samples. To achieve this, prospective collection of pre-treatment, mid-treatment and post-treatment blood samples will be undertaken. Our research proposal is designed to deliver a statistically powered and evidence-based resource that will enable a detail understanding of the relationships between CH, treatment exposures and subsequent risk of tMN. Our findings will enable the development of genomic based risk assessment of tMN in solid tumor patients. This will guide rational treatment decisions for solid tumor patients across a variety of primary sites aimed at minimization of tMN risk, a major barrier to long-term survival.