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..

摘要 对世界贸易中心(WTC)的恐怖袭击造成了前所未有的环境风险 含有已知和可疑致癌物质(包括多环芳烃)的气雾化粉尘和气体 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称 纽约市(FDNY)暴露于WTC的消防局消防员癌症病例过剩，(2， 3)白血病和多发性骨髓瘤的发病率呈上升趋势。我们继续前瞻性地 跟踪纽约消防局整个消防队的癌症发病率，并建立了一个样本生物资料库 由2000多名接触WTC的消防员和非WTC消防员的分级血液成分和血清组成- 暴露了消防员的控制。利用这一队列，我们对781名暴露于WTC的人进行了初步研究 消防员表现出明显更高的未确定的单克隆性丙种球蛋白病患病率 MGUS是多发性骨髓瘤的先兆。(四)深入开展有针对性的工作 飞行员队列中接触WTC的消防员(N=481)和年龄匹配的非WTC接触者的基因组测序 消防员控制(N=52)。我们观察到克隆性造血(CH)和白血病相关的高发生率 暴露于WTC的消防员中的突变(57/481；12%)。对照组的突变率为2%， 与已发表的研究中年龄匹配的对照组相似(5，6)。克隆性造血(CH)是一种获得 与白血病相关的体细胞突变会增加血液病和全因癌症的风险 死亡率。在接触WTC的消防员中发现的突变影响了DNMT3A、TET2、TP53、剪接和其他 常见的反复突变的基因。这些突变表明CH的发生率很高，而其他队列中的CH具有 已被证明与发生髓系肿瘤、炎症和心脏疾病的风险有关 疾病。我们现在建议全面确定暴露于纽约联邦储备银行的大型WTC中CH的患病率 收集和研究WTC颗粒物(WTC-)造成损害的分子和细胞机制 PM)。目的1将使用深度靶向测序确定克隆性造血突变的流行率 一大批接触WTC的消防员和2名对照样本(非WTC消防员和非WTC消防员 消防员年龄与对照组匹配)。突变将与WTC水平等临床变量相关 暴露、年龄、连续血细胞计数、吸烟史等临床特征。目标2将决定 WTC颗粒物对小鼠体内克隆性造血发育的功能影响 具有常见TET2和DNMT3A基因突变的模型。最后，目标3将确定WTC-PM的效果 暴露于单分子水平上的细胞变化以评估DNA的机制和大小 暴露的细胞受损。这些结果将进一步加深我们对这一机制的理解 环境暴露会导致基因组的不稳定。重要的是，及早发现CH突变将使 对接触WTC的消防员进行有针对性的临床评估，使早期诊断和潜在疾病改变成为可能 干预--NIOSH WTC卫生项目“从研究到护理”翻译模式的中心目标。