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

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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.