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

癌前突变情况和进展为血液癌的危险因素

• 批准号: 10378484
• 负责人: Pinkal Desai
• 金额: $ 66.51万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2026-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10378484
• 关键词: Acute Myelocytic Leukemia; Age; Age-Years; Alleles; Ascorbic Acid; Blood; Blood Banks; Blood specimen; Cells; Chronic Lymphocytic Leukemia; Clinical; Clinical Trials; Clonal Expansion; Cohort Studies; DNA; Data; Development; Diagnosis; Disease; Epidemiology; Future; Genes; Genomics; Glucose; Goals; Health Care Costs; Hematologic Neoplasms; Hematology; Hematopoiesis; Individual; Inflammation; Inflammatory; Intercept; Intervention; JAK2 gene; Kinetics; Large-Scale Sequencing; Link; Malignant Neoplasms; Medicine; Metabolic; Metabolic Pathway; Methods; Molecular; Monitor; Morbidity - disease rate; Multiple Myeloma; Mutation; Nature; Obesity; Outcome; Participant; Pattern; Persons; Plasma; Positioning Attribute; Precancerous Conditions; Predictive Factor; Prevalence; Prevention; Prevention strategy; Prospective cohort; Publishing; Randomized Controlled Trials; Reporting; Research; Risk; Risk Assessment; Risk Factors; Sampling; Shapes; Somatic Mutation; Specimen; Spliceosomes; TP53 gene; Time; United States; Woman; Women' s Health; Work; adjudicate; base; cancer diagnosis; case control; cell growth; chemokine; cohort; deep sequencing; follow-up; founder mutation; high risk; improved; inflammatory marker; innovation; insight; leukemia/lymphoma; metabolomics; modifiable risk; mortality; multidisciplinary; novel; peripheral blood; population based; pre-clinical; premalignant; prevent; preventive intervention; prospective; research study; risk prediction; statistics; tumorigenesis

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.

抽象的 克隆造血（CH）被定义为在外周血中可检测到的可获得突变的存在 没有血液系统恶性肿瘤（HM）的正常健康个体已通过测序很好地表征 基于人群的队列研究。 CH的存在与事件HMS的> 12倍相关。更多的 需要数据来描述特定疾病和突变的特定风险以及可能影响的因素 从CH到HM的进化轨迹。我们在先前的工作中已经证明了Whi的参与者 开发AML的人携带突变的可能性是中位数9。6年的四倍。 与对照组（70％对30％或4.0、95％C.I. 2.5-6.3）相比，AML与TP53，IDH1/2和 剪接体基因与AML风险增加高度相关，并且在对照组之间很少存在。这 长期目标是确定有助于HM发展的突变和细胞 - 超支因素 因此为HM截距和预防的未来临床试验提供了基础。已发布的数据指示 代谢因素和影响CH扩展的能力。我们的中心假设是 可以预期的那种预测HM发展的突变，炎症和代谢因素 确定，从而改善了风险评估。我们将利用收集的外周血样本 妇女健康倡议（WHI）队列的基线，前瞻性跟随168,808名妇女 中位数为10。8年。所有癌症结果均通过中央审查调整。我们的具体目标将 确定以下内容：（1）基线前HM突变的风险和特定HM的发展 参加者的参与者。我们将选择400例HM（200例慢性淋巴细胞性白血病（CLL）和200例 多发性骨髓瘤的病例）以及年龄匹配的400个对照，这些对照在随访期间未产生HM （2）确定代谢和炎症异常在促进CH膨胀和 影响从CH到HM的发展。我们的研究很重要，因为没有已知的干预 防止或延迟CH向HM的进展以及一般，前瞻性，随机，控制的策略 预防策略的试验需要多年的随访才能得出确定的结论。我们的研究愿意 基于突变，炎症和代谢因素以及 为监视具有最高风险HM的人的人提供理由。而且，这些数据将 提供有关防止HM发作的干预策略的新见解。拟议的研究是 研究突变和代谢以及影响的炎症因素的创新性 使用大量女性的长期数据将CH到HM的进展。