EARLY DETECTION OF CLONAL HEMATOPOIESIS AND LEUKEMIA ASSOCIATED MUTATIONS IN WTC EXPOSED FIREFIGHTERS AFTER THE 9/11 ATTACKS

9/11 袭击后世贸中心暴露的消防员中克隆性造血和白血病相关突变的早期检测

• 批准号: 10459187
• 负责人: DAVID J PREZANT
• 金额: $ 48.86万
• 依托单位: ALBERT EINSTEIN COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10459187
• 关键词: EARLY; DETECTION; CLONAL; HEMATOPOIESIS; LEUKEMIA

ABSTRACT The terrorist attacks on the World Trade Center (WTC) created an unprecedented environmental exposure to WTC aerosolized dust and gases that contained known and suspected carcinogens including polycyclic aromatic hydrocarbons, polychlorinated biphenyls, furans, dioxins and asbestos. Studies from our group have reported an excess of cancer cases in the WTC-exposed Fire Department of the City of New York (FDNY) firefighters,(2, 3) including a trend towards higher incidence of leukemia and multiple myeloma. We continue to prospectively follow the entire FDNY cohort of firefighters for cancer incidence and have built a biorepository of samples consisting of fractionated blood components and serum from 2000+ WTC-exposed firefighters and non-WTC- exposed firefighter controls. Using this cohort, we have conducted preliminary studies in 781 WTC-exposed firefighters that demonstrate a significantly higher prevalence of monoclonal gammopathy of undetermined significance (MGUS), a precursor for multiple myeloma. (4) Furthermore, we have conducted deep targeted genome sequencing of a pilot cohort of WTC-exposed firefighters (N=481) and non-WTC-exposed age matched firefighter controls (N=52). We observed a high incidence of Clonal hematopoiesis (CH) and leukemia associated mutations (57/481; 12%) in WTC-exposed firefighters. The rate of mutations in controls was 2% and is comparable to age matched controls in published studies (5, 6). Clonal hematopoiesis (CH) is acquisition of leukemia associated somatic mutations that carry increase risk of hematologic cancer as well as all-cause mortality. The mutations seen in WTC-exposed firefighters affected DNMT3A, TET2, TP53, Splicing and other commonly recurrently mutated genes. These mutations suggest a high rate of CH, and CH in other cohorts has been shown to be associated with risk for development of myeloid neoplasms, inflammatory conditions and heart diseases. We now propose to comprehensively determine the prevalence of CH in a large FDNY WTC-exposed cohort and study the molecular and cellular mechanisms of damage caused by WTC particulate matter (WTC- PM). Aim 1 will determine the prevalence of clonal hematopoiesis mutations using deep targeted sequencing in a large cohort of WTC-exposed firefighter and 2 cohorts of control samples (non-WTC firefighters and non- firefighter age matched controls). Mutations will be correlated with clinical variables such as level of WTC exposure, age, serial blood counts, smoking history and other clinical characteristics. Aim 2 will determine the functional effects of WTC particulate matter on development of clonal hematopoiesis in vivo by using mouse models with commonly mutated TET2 and DNMT3A genes. Lastly, aim 3 will determine the effect of WTC-PM exposure on cellular changes at the single molecule level to assess the mechanisms and magnitude of DNA damage in exposed cells. These results will further our understanding on the mechanism via which environmental exposures lead to genomic instability. Importantly, early detection of CH mutations will enable targeted clinical evaluations of WTC-exposed firefighters, enabling early diagnosis and potential disease altering interventions – a central goal of the NIOSH WTC Health Program's “Research to Care” translational model..

抽象的 恐怖袭击世界贸易中心（WTC）造成了前所未有的环境暴露 WTC的尘埃和气体，其中包含已知和可疑的致癌物，包括多环芳烃 碳氢化合物，多氯联苯，呋喃，二恶英和石棉。我们小组的研究报告了 在纽约市（FDNY）消防员的WTC暴露消防局中，超过癌症病例，（2， 3）包括一种趋向于白血病和多发性一次到多发性骨髓瘤事件的趋势。我们继续前景 跟随整个FDNY群体进行癌症事件，并建立了样本的生物措施 由2000+ WTC暴露的消防员和非WTC-的分馏血成分和血清组成 裸露的消防员控件。使用此队列，我们​​在781 WTC暴露中进行了初步研究 消防员表现出明显更高的单克隆性伽马病的患病率不确定 显着性（MGU），多发性骨髓瘤的前体。 （4）此外，我们已经进行了深入的目标 WTC暴露的消防员（n = 481）和非WTC暴露年龄匹配的试验队列的基因组测序 消防员控制（n = 52）。我们观察到了一系列高的克隆造血（CH）和白血病相关的 暴露于WTC的消防员中的突变（57/481; 12％）。对照中突变的速率为2％，为 在已发表的研究中与年龄匹配的对照相媲美（5，6）。克隆造血（CH）是 白血病相关的躯体突变，这些突变增加了血液学癌的风险以及全因 死亡。在暴露于WTC的消防员中看到的突变影响了DNMT3A，TET2，TP53，拼接和其他 通常复发突变的基因。这些突变表明其他队列中的CH速率很高，CH具有 我们被证明与发生髓样肿瘤，炎症状况和心脏的风险有关 疾病。现在，我们建议在大型FDNY WTC暴露中全面确定CH的患病率 队列和研究由WTC颗粒物质引起的损伤的分子和细胞机制（WTC- 下午）。 AIM 1将使用深层靶向测序确定克隆造血突变的患病率 大量暴露于WTC的消防员和2个对照样本（非WTC消防员和非 - 消防员年龄匹配的控件）。突变将与临床变量（例如WTC水平）相关 暴露，年龄，连环血数，吸烟史和其他临床特征。 AIM 2将确定 WTC的功能影响特定物质对使用小鼠在体内发育对克隆造血的发展 具有通常突变的TET2和DNMT3A基因的模型。最后，AIM 3将确定WTC-PM的效果 在单分子水平的细胞变化上暴露于评估DNA的机制和幅度 暴露细胞的损害。这些结果将进一步我们对通过的机制的理解 环境暴露导致基因组不稳定性。重要的是，对CH突变的早期检测将实现 对WTC暴露消防员的有针对性临床评估，使早期诊断和潜在疾病改变 干预措施 - NIOSH WTC健康计划的“护理研究”翻译模型的核心目标。