Florida International University FIU Digital Commons FIU Electronic Theses and Dissertations University Graduate School 11-14-2011 The otP ential Role of Environmental Exposures and Genomic Signaling in Development of Central Nervous System Tumors Brian W. Kunkle Florida International University, [email protected] DOI: 10.25148/etd.FI11120809 Follow this and additional works at: https://digitalcommons.fiu.edu/etd Recommended Citation Kunkle, Brian W., "The otP ential Role of Environmental Exposures and Genomic Signaling in Development of Central Nervous System Tumors" (2011). FIU Electronic Theses and Dissertations. 524. https://digitalcommons.fiu.edu/etd/524 This work is brought to you for free and open access by the University Graduate School at FIU Digital Commons. It has been accepted for inclusion in FIU Electronic Theses and Dissertations by an authorized administrator of FIU Digital Commons. For more information, please contact [email protected]. FLORIDA INTERNATIONAL UNIVERSITY Miami, Florida THE POTENTIAL ROLE OF ENVIRONMENTAL EXPOSURES AND GENOMIC SIGNALING IN DEVELOPMENT OF CENTRAL NERVOUS SYSTEM TUMORS A dissertation submitted in partial fulfillment of the requirements for the degree of DOCTOR OF PHILOSOPHY in PUBLIC HEALTH by Brian William Kunkle 2011 To: Interim Dean Michelle Cicazzo Robert Stempel College of Public Health and Social Work This dissertation written by Brian William Kunkle, and entitled The Potential Role of Environmental Exposures and Genomic Signaling in Development of Central Nervous System Tumors, having been approved in respect to style and intellectual content, is referred to you for judgment. We have read this dissertation and recommend that it be approved. ____________________________________ Changwon Yoo ____________________________________ Quentin Felty ____________________________________ Nasar Ahmed ____________________________________ Deodutta Roy, Major Professor Date of Defense: November 14, 2011 The dissertation of Brian William Kunkle is approved. ____________________________________ Interim Dean Michelle Cicazzo Robert Stempel College of Public Health and Social Work ____________________________________ Dean Lakshmi N. Reddi University Graduate School Florida International University, 2011 ii © Copyright 2011 by Brian William Kunkle All rights reserved. iii ACKNOWLEDGMENTS It is my pleasure to acknowledge some of the colleagues, family and friends who have helped complete this dissertation. I would like to express my deepest gratitude to my advisor, Dr. Deodutta Roy, for his excellent guidance, support, patience, and encouragement during the entire dissertation process. I would also like to thank Dr. Changwon Yoo, Dr. Nasar Ahmed, and Dr. Quentin Felty for guiding my research for the past several years and helping me to develop my background in bioinformatics, gene networking, epidemiology, and biochemistry. Their expertise and assistance proved invaluable at critical points in this dissertation. Financial support from the Stempel College of Public Health & Social Work, as well as the Florida International University Doctoral Evidence Acquisition Fellowship, was greatly appreciated and completion of this dissertation would not have been possible in its absence. Finally, I would like to thank my family and friends. Their support and encouragement was a source of strength for me during this long process, and I greatly value their love and friendship. iv ABSTRACT OF THE DISSERTATION THE POTENTIAL ROLE OF ENVIRONMENTAL EXPOSURES AND GENOMIC SIGNALING IN DEVELOPMENT OF CENTRAL NERVOUS SYSTEM TUMORS by Brian William Kunkle Florida International University, 2011 Miami, FL Professor Deodutta Roy, Major Professor The etiology of central nervous system tumors (CNSTs) is mainly unknown. Aside from extremely rare genetic conditions, such as neurofibromatosis and tuberous sclerosis, the only unequivocally identified risk factor is exposure to ionizing radiation, and this explains only a very small fraction of cases. Using meta-analysis, gene networking and bioinformatics methods, this dissertation explored the hypothesis that environmental exposures produce genetic and epigenetic alterations that may be involved in the etiology of CNSTs. A meta-analysis of epidemiological studies of pesticides and pediatric brain tumors revealed a significantly increased risk of brain tumors among children whose mothers had farm-related exposures during pregnancy. A dose response was recognized when this risk estimate was compared to those for risk of brain tumors from maternal exposure to non- agricultural pesticides during pregnancy, and risk of brain tumors among children exposed to agricultural activities. Through meta-analysis of several microarray studies which compared normal tissue to astrocytomas, we were able to identify a list of 554 genes which were differentially expressed in the majority of astrocytomas. Many of these genes have in fact been implicated in development of astrocytoma, including EGFR, HIF-1α, c-Myc, WNT5A, and IDH3A. Reverse engineering of these 554 genes using Bayesian network analysis produced a gene network for each grade of astrocytoma (Grade I-IV), and ‘key genes’ within each grade were identified. Genes found to be most influential to development of the highest grade of astrocytoma, Glioblastoma multiforme (GBM) were: COL4A1, EGFR, BTF3, MPP2, RAB31, CDK4, CD99, ANXA2, TOP2A, and SERBP1. Lastly, bioinformatics analysis of environmental databases and curated published results on GBM was able to identify numerous potential pathways and gene- environment interactions that may play key roles in astrocytoma development. Findings from this research have strong potential to advance our understanding of the etiology and susceptibility to CNSTs. Validation of our 'key genes' and pathways could potentially lead to useful tools for early detection and novel therapeutic options for these tumors. ii TABLE OF CONTENTS CHAPTER PAGE LITERATURE REVIEWS ..................................................................................................4 Manuscript 1: Gene-environment interaction and susceptibility to pediatric brain tumors .4 Manuscript 2: Environment, genetic and epigenetic alterations and pediatric central nervous system tumors .......................................................................................................56 HYPOTHESIS AND SPECIFIC AIMS ..........................................................................132 RESEARCH MANUSCRIPTS ........................................................................................133 Manuscript 3: Early life exposure of the brain to pesticides and development of childhood brain cancer: A Meta-analysis .........................................................................................133 Manuscript 4: Identifying gene alterations required for the development of astrocytoma ..........................................................................................................................................151 Manuscript 5: Modeling gene-environment interaction in Glioblastoma Multiforme via an integrated bioinformatics approach ..................................................................................192 APPENDIX ......................................................................................................................216 VITA .................................................................................. Error! Bookmark not defined. iii LIST OF TABLES TABLE PAGE Table 1-1. Summary of overall risk evaluation for selected environmental exposures in relation to pediatric brain tumors. ......................................................................................13 Table 1-2. Disorders and mutations in genes causing familial forms of pediatric brain tumors. ...............................................................................................................................20 Table 1-3. Summary of gene-environment interaction studies conducted on pediatric and adult brain tumors. .............................................................................................................38 Table 2-1. Common susceptibility genes of pediatric medulloblastoma. ..........................65 Table 2-2. Common susceptibility genes of pediatric astrocytoma. ..................................77 Table 2-3. Common susceptibility genes of neuroblastoma. .............................................87 Table 3-1. Characteristics of studies included in the meta-analyses of parental pesticide exposure and risk of childhood brain tumor development. ..............................................140 Table 3-2. Summary of results of meta-analyses of the association between pesticides and childhood brain tumors. ...................................................................................................141 Table 4-1. List of Oncomine studies in meta-analysis of Astrocytoma vs. Normal Studies ..........................................................................................................................................164 Table 4-2. Significant over-represented GO Terms for differentially expressed genes in Astrocytoma. ....................................................................................................................165 Table 4-3. Significant under-represented GO Terms for differentially expressed genes in Astrocytoma. ....................................................................................................................166 Table 4-4. Sample statistics