Pre-malignant mutation landscape and risk factors for progression to hematologic cancers

摘要 克隆性造血(CH)定义为在患者外周血中检测到获得性突变 没有恶性血液病(HM)的正常健康个体已经通过测序获得了很好的特征 基于人群的队列研究。CH的存在与最终HMS的风险增加12倍相关。更多 需要数据来描述疾病特定和突变特定的风险，以及可能影响 从CH到HM的演化轨迹。我们在之前的工作中已经证明，WHI的参与者 罹患AML的人携带突变的可能性是AML的四倍，发病前的中位数为9.6年 急性髓系白血病与对照组(70%比30%，OR 4.0，95%C.I.2.5-6.3)相比，TP53、IDH1/2和 剪接体基因与急性髓系白血病风险增加高度相关，在对照组中很少出现。这个 长期的目标是找出导致HM发生的突变因素和细胞外在因素。 从而为今后HM截留和预防的临床试验提供了依据。公布的数据表明 代谢因素和炎症因素影响CH扩张的能力。我们的中心假设是 预测HM发展的突变、炎症和代谢因素可以是前瞻性的 已确定，从而能够改进风险评估。我们将利用在以下地点收集的外周血液样本 妇女健康倡议(WHI)队列的基线，前瞻性地跟踪了168,808名妇女 中位数为10.8年。所有的癌症结果都由中央评审来判定。我们的具体目标将是 确定以下内容：(1)基线前HM突变的风险和发生特定HM的风险 世界卫生倡议的参与者。我们将选择400例HM(200例慢性淋巴细胞白血病(CLL)和200例 2例多发性骨髓瘤)和年龄匹配的400名对照组，在WHI随访期间没有发生HM (2)确定代谢和炎症异常在促进CH扩张和 影响着从CH到HM的进程。我们的研究意义重大，因为目前还没有已知的干预措施 预防或延缓CH向HM进展的策略，总体上是前瞻性的、随机的、受控的 预防战略的试验需要多年的后续行动才能得出明确的结论。我们的研究将 根据突变、炎症和代谢因素确定HM的最高风险个体 为监测慢性肝炎高危人群提供依据。此外，这些数据将 为预防HM发病的干预策略提供新的见解。拟议的研究是 在研究突变、新陈代谢和炎症因素方面具有创新性 使用大量女性队列的长期数据进行CH向HM的进展。

ABSTRACT Clonal hematopoesis (CH) defined as the presence of acquired mutations detectable in peripheral blood of normal healthy individuals without hematologic malignancies (HM) has been well characterized by sequencing population based cohort studies. The presence of CH is associated with >12-fold risk of eventual HMs. More data are needed to delineate disease specific and mutation specific risk as well as factors that might shape the evolutionary trajectory from CH to HM. We have demonstrated in our prior work that participants in the WHI who developed AML were four times more likely to harbor a mutation a median of 9.6 years before the onset of AML compared to controls (70% vs. 30%, OR 4.0, 95% C.I. 2.5-6.3) with mutations in TP53, IDH1/2, and spliceosome genes being highly associated with increased risk of AML and rarely present among controls. The long-term goal is to identify both mutational and cell-extrinsic factors that contribute to the development of HM and thus provide the basis for future clinical trials of HM interception and prevention. Published data indicate the ability of metabolic factors and inflammation to influence the expansion of CH. Our central hypothesis is that mutational, inflammatory and metabolic factors that predict the development of HM can be prospectively identified, thus enabling improved risk assessment. We will utilize peripheral blood samples collected at baseline from the Women’s Health Initiative (WHI) cohort that prospectively followed 168,808 women for a median of 10.8 years. All cancer outcomes were adjudicated by central review. Our specific aims will determine the following: (1) the risk of baseline pre-HM mutations and development of specific HM among participants in the WHI. We will select 400 cases of HM (200 chronic lymphocytic leukemia (CLL) and 200 cases of multiple myeloma) along with age matched 400 controls that did not develop HM during WHI follow up (2) To determine the impact of metabolic and inflammatory abnormalities in promoting CH expansion and impacting the progression from CH to HM. Our study is significant because there is no known intervention strategy to prevent or delay the progression of CH to HM and in general, prospective, randomized, controlled trials of prevention strategies require many years of follow-up to reach definitive conclusions. Our study will establish individuals at highest risk of HM based on mutational, inflammatory and metabolic factors and provide grounds for monitoring people individuals with CH at highest risk of HM. Moreover, these data will provide novel insight into intervention strategies to prevent the onset of HM. The proposed research is innovative in investigating mutational and metabolic as well as inflammatory factors that impact the progression of CH to HM using long term data from a large cohort of women.