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，如橙子剂（AO）和燃烧坑的烟雾，是重要的暴露， 冲突地区的军事和平民人口，并与淋巴系统的发展有关。 恶性肿瘤AO是一种除草剂，被致癌物2，3，7，8-四氯二苯并-p- 二恶英（TCDD）作为合成过程中的副产物。AO被用来砍伐越南的丛林， 朝鲜非军事区。虽然AO不再使用，但其影响仍然相关，因为它的长半- 其寿命几乎为10年，甚至在20年后在人血清中检测到。临床前研究表明， 芳香烃受体（AHR，二恶英受体）途径的激活导致 淋巴恶性肿瘤，因为抑制细胞凋亡和/或免疫抑制。其次，慢性 暴露于TCDD通过改变病理生理学上的转录而使表观遗传功能失调， 参与肿瘤发生的重要蛋白质。最后，另一个有趣的联系可以建立在以下基础上： 性与女性相比，类肉瘤恶性肿瘤在男性中普遍更普遍，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激素作用。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， AHR和ER之间的结合、ER降解增加以及介导CYP 1A 1的上调 雌激素代谢总之，这些机制可能构成了增加的免疫缺陷的病理生理学基础。 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表观遗传调控的发展和进展， 淋巴恶性肿瘤，那么这些患者将有表观遗传基因突变或表现出更大程度的 与对照组相比，肿瘤组织中病理生理相关基因的DNA甲基化变化。 这些发现可用作生物标志物，以确定哪些人可能从靶向治疗中获益， 未来的研究。目前，已批准用于血液恶性肿瘤的表观遗传治疗， 低甲基化剂和/或组蛋白去乙酰化酶抑制剂，其可以针对大多数 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（SA 1）：创建预测模型 使用来自未来百万退伍军人计划的临床和遗传数据库， 这些因素可能会导致淋巴恶性肿瘤的发展。入组患者填写调查表 关于病史，军事暴露，生活方式和药物，并提交血液进行基因组测序， 与我们的假设相关此外，VA医疗记录和国家死亡指数的数据 可以充分探索病人的烦恼。具体目标2（SA 2）：使用现有的遗留病理学 比较暴露相关淋巴结转移患者的表观遗传学和免疫组织化学变化 恶性肿瘤与未暴露者。这些发现将与临床结果相关， 作为生物标志物，用于预测未来研究对靶向治疗的反应。具体目标3（SA 3）：确认 我们在区域VA医院的扩展队列中从SA 2中获得的发现，利用我们的既定研究 协作我们的研究可能会找出导致二恶英的特定病理生理机制， 诱发淋巴恶性肿瘤。我们还希望确定特定的和可操作的基因/蛋白质/途径， 可以在未来的精准肿瘤临床试验中进行治疗靶向。