Epigenetic Dysregulation, Genetic Mutations, And Outcomes Of Lymphoid Malignancies Related To Agent Orange And Burn Pit Exposures Compared To Unexposed Case-Matched Controls

与未暴露的病例匹配对照相比，与橙剂和烧伤坑暴露相关的表观遗传失调、基因突变和淋巴恶性肿瘤的结果

• 批准号: 10587826
• 负责人: Helen Ma
• 金额: --
• 依托单位: VETERANS HEALTH ADMINISTRATION
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-01 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10587826
• 关键词: Age; Antibodies; Aryl Hydrocarbon Receptor; B-Cell Lymphomas; Binding; Bioinformatics; Biological Markers; Biopsy; Blood; CYP1A1 gene; Cessation of life; Chemicals; Chronic; Chronic Lymphocytic Leukemia; Clinical; Clinical Data; Clinical Trials; Clinical Trials Design; Collaborations; Conflict (Psychology); Core Facility; DNA Methylation; DNA Sequence Alteration; Data; Data Correlations; Data Set; Databases; Detection; Development; Diagnosis; Dioxins; Enrollment; Environmental Carcinogens; Environmental Exposure; Epigenetic Process; Estrogen Metabolism; Estrogen Receptor alpha; Estrogen Receptors; Estrogens; Exhibits; Exposure to; Future; Genes; Genetic; Genetic Code; Genetic Databases; Genetic Transcription; Genomics; Half-Life; Health; Health system; Healthcare Systems; Hematologic Neoplasms; Hematopoietic Neoplasms; Herbicides; Histone Deacetylase Inhibitor; Hodgkin Disease; Hormonal; Hospitals; Human; Immunosuppression; Incidence; Indolent; Inhibition of Apoptosis; Korea; Life Style; Ligands; Los Angeles; Lymphoma; Lymphomagenesis; Malignant lymphoid neoplasm; Marines; Mediating; Medical History; Medical Records; Methylation; Middle East; Military Personnel; Modeling; Mutation; Oncogenes; Outcome; Pathologist; Pathology; Pathway interactions; Patients; Peripheral; Pharmaceutical Preparations; Population; Probability; Proteins; Public Health; Regulation; Research; Risk; Risk Factors; Sample Size; Sampling; Serum; Services; Smoke; Specimen; Stains; Surveys; T-Cell Lymphoma; Techniques; Testing; Tetrachlorodibenzodioxin; Tissues; Translational Research; Tumor Tissue; Up-Regulation; Validation; Veterans; Vietnam; Woman; agent orange; arm; burn pit; cancer clinical trial; cancer type; carcinogenicity; chemical carcinogen; clinical database; cohort; comparison control; development of lymphoid malignancy; epigenetic drug; epigenetic regulation; indexing; large cell Diffuse non-Hodgkin' s lymphoma; mathematical model; men; mortality; novel; precision oncology; preclinical study; predicting response; predictive modeling; programs; progression risk; prospective; protective effect; rational design; risk prediction; routine care; sex; targeted treatment; tumor; tumorigenesis

Environmental carcinogens, such as Agent Orange (AO) and smoke from burn pits, are important exposures to the military and civilian populations in theaters of conflict and have been related to development of lymphoid malignancies. AO was an herbicide that was contaminated with the carcinogenic 2,3,7,8-tetrachlorodibenzo-p- dioxin (TCDD) as a byproduct during synthesis. AO was used to deforest the jungles of Vietnam and the demilitarized zone of Korea. Though AO is no longer used, its impact remains relevant because of its long half- life of almost ten years and its detection in human serum even after 20 years. Preclinical studies show that activation of the aryl hydrocarbon receptor (AHR, the dioxin receptor) pathway leads to the development of lymphoid malignancies because of inhibition of apoptosis and/or immune suppression. Secondly, chronic exposure to TCDD dysregulates epigenetic functions by altering the transcription of pathophysiologically important proteins involved in oncogenesis. Finally, another interesting connection can be made on the basis of sex. Lymphoid malignancies are universally more prevalent in men compared to women, but the mechanism is poorly understood. One reason could be that estrogen may exert protective hormonal effects. Dioxin exposure and activation of the AHR pathway has been associated with decreased levels of estrogen receptor (ER) due to binding between AHR and ER, increased degradation of ER, and upregulation of CYP1A1, which mediates estrogen metabolism. Together, these mechanism(s) may form the pathophysiological basis for the increased incidence and poorer clinical outcomes of lymphoid malignancies following environmental exposures. We hypothesize that if chemical carcinogens alter epigenetic regulation in the development and progression of lymphoid malignancies, then these patients will have mutations in epigenetic genes or exhibit a greater degree of change in DNA methylation of pathophysiologically relevant genes in the tumor tissue compared to controls. These findings can be used as biomarkers to identify who may benefit from treatment with targeted therapies in future studies. Currently there are approved epigenetic treatments for hematologic malignancies with hypomethylating agents and/or histone deacetylase inhibitors, which could be tailored to patients who will most likely benefit. We will test our hypothesis via three specific aims. Specific Aim 1 (SA1): Create a predictive model using the clinical and genetic database from the prospective Million Veterans Program to determine which risk factors are likely to contribute to the development of lymphoid malignancies. Patients who enroll fill out surveys about medical history, military exposures, lifestyle, and medications and submit blood for genomic sequencing, which are relevant to our hypothesis. In addition, data from VA medical records and the National Death Index are available to fully explore the patient exposome. Specific Aim 2 (SA2): Use existing, left-over pathology specimens to compare epigenetic and immunohistochemical changes in patients with exposure related lymphoid malignancies versus those without exposure. These findings will be correlated with clinical outcomes and be used as biomarkers to predict response to targeted therapies for future studies. Specific Aim 3 (SA3): Confirm our findings from SA2 in an expansion cohort from regional VA hospitals, leveraging our established research collaboration. Our studies are likely to identify specific pathophysiological mechanism(s) responsible for dioxin- induced lymphoid malignancies. We also hope to identify specific and actionable genes/proteins/pathways that can be targeted therapeutically in future precision oncology clinical trials.

环境致癌物，例如橙剂 (AO) 和燃烧坑产生的烟雾，是重要的暴露途径 冲突地区的军事和平民人口，与淋巴组织的发育有关 恶性肿瘤。 AO 是一种除草剂，被致癌物质 2,3,7,8-四氯二苯并-p-污染 二恶英 (TCDD) 作为合成过程中的副产物。 AO 被用来砍伐越南和美国的丛林 朝鲜非军事区。尽管 AO 已不再使用，但由于其半衰期较长，其影响仍然重要。 寿命近十年，20年后仍可在人血清中检测到。临床前研究表明 芳基碳氢化合物受体（AHR，二恶英受体）途径的激活导致 由于细胞凋亡抑制和/或免疫抑制而导致淋巴恶性肿瘤。其次，慢性 暴露于 TCDD 通过改变病理生理学转录来调节表观遗传功能 参与肿瘤发生的重要蛋白质。最后，可以在以下基础上建立另一个有趣的联系： 性别。与女性相比，淋巴恶性肿瘤在男性中普遍更为普遍，但其机制是 不太了解。原因之一可能是雌激素可能发挥保护性荷尔蒙作用。二恶英暴露 AHR 通路的激活与雌激素受体 (ER) 水平的降低有关，这是由于 AHR 和 ER 之间的结合、ER 降解增加以及 CYP1A1 的上调，从而介导 雌激素代谢。总之，这些机制可能构成增加的病理生理学基础。 环境暴露后淋巴恶性肿瘤的发病率和较差的临床结果。 我们假设，如果化学致癌物改变了癌症发生和进展过程中的表观遗传调控， 淋巴恶性肿瘤，那么这些患者将出现表观遗传基因突变或表现出更大程度的突变 与对照相比，肿瘤组织中病理生理相关基因的 DNA 甲基化变化。 这些发现可以用作生物标志物，以确定哪些人可以从靶向治疗中受益 未来的研究。目前已批准用于血液恶性肿瘤的表观遗传学治疗 低甲基化剂和/或组蛋白脱乙酰酶抑制剂，可以针对最需要的患者量身定制 可能的好处。我们将通过三个具体目标来检验我们的假设。具体目标 1 (SA1)：创建预测模型 使用前瞻性百万退伍军人计划的临床和遗传数据库来确定哪些风险 因素可能会导致淋巴恶性肿瘤的发生。注册的患者填写调查问卷 有关病史、军事经历、生活方式和药物的信息，并提交血液进行基因组测序， 与我们的假设相关。此外，来自 VA 医疗记录和国家死亡指数的数据 可用于充分探索患者暴露组。具体目标 2 (SA2)：利用现有的、遗留的病理学 比较暴露相关淋巴患者的表观遗传和免疫组织化学变化的标本 恶性肿瘤与未接触过的恶性肿瘤。这些发现将与临床结果相关并被 用作生物标志物来预测未来研究对靶向治疗的反应。具体目标 3 (SA3)：确认 我们利用我们既定的研究，在 VA 地区医院的扩展队列中得出 SA2 的研究结果 合作。我们的研究可能会确定导致二恶英的特定病理生理机制 诱发淋巴系统恶性肿瘤。我们还希望找出特定且可操作的基因/蛋白质/途径， 可以在未来的精准肿瘤学临床试验中进行靶向治疗。