Identifying gene alterations required for the development of astrocytoma

Brian Kunkle, Changwon Yoo, Quentin Felty, Deodutta Roy

Research output: Chapter in Book/Report/Conference proceedingConference contribution

Abstract

A growing body of evidence suggests that there are critical periods of time extending from conception to puberty when the central nervous system in children may be more affected by environmental toxin exposures. These exposures may likely interact with the genome/epigenome of the fetus or young child to produce alterations in their genetic makeup which can predispose to development of disease, including glial tumors. However, very few studies to date have investigated gene-environment interaction in relation to the development of glial tumors. Interactions of environmental factors with genetic and epigenetic changes are expected to contribute in the development of the particular type of glial tumor in an individual. Glial tumors are usually broken down into more specific subtypes based on their predicted cell type of origin. The most common glial tumors include astrocytoma (originated from astrocytes), oligodendroglioma (originated from oligodendrocytes), brain stem glioma (originated from brain stem cells), and ependymoma (originated from ependymal cells). The assessment of gene- environment interaction in glial tumors has been more complex because of the lack of sound molecular epidemiological studies with a more complete picture of individual cancer risk associated with environmental exposure and genetic analysis. Our goal in this study was to identify gene-environment interactions that are critical in the development of glioblastoma multiforme (GBM), the most common and aggressive type of human brain tumor. A GBM is a grade IV astrocytoma. We have used environmental bioinformatic resources for investigation of gene-environment interactions in the development of astrocytoma. We also combined these analytic approaches through first combining available microarray data on astrocytoma using a meta-analysis approach, and then conducting gene pathway networking analysis on results of this meta-analysis. Genes responsive to environmental exposures were identified using the Environmental Genome Project, Comparative Toxicology, and Seattle SNPs databases. These genes were then compared to a curated list of genes altered in GBM. The list of genes responsive to the environment and important to GBM was then further investigated using gene networking tools such as RSpider and Cytoscape. Overlapping of final list of GBM alterations with the environmental genes found 173 genes that had an environmental exposure link and were altered in glioblastoma. Of these 173 genes, a Pubmatrix search found that 65 overlapping genes had not been previously assessed in glioblastoma research. A specific search for chemicalgene interactions producing mutagenesis in our genes found 226 results. The main biological functions of these genes included Signaling by Nerve Growth Factor (NGF), DNA Repair, Integrin Cell Surface Interactions, Biological Oxidations, Apoptosis, Synaptic Transmission, Cell Cycle Checkpoints, and Arachidonic Acid Metabolism. Four separate analyses were run in Banjo in order to search for genes critical for Grade I Astrocytoma development. Top Bayesian network and Markov blanket genes identified for Grade I Pilocytic Astrocytoma were IGFB5, TIMP4, SSR2, LPL, DUSP7, GABRA5, SH3GL3, C1S, ANK3, HLAA, EIF4A1, PTGER3, CCND2. Many of the genes identified in this study have in fact been implicated in the development of astrocytoma, including EGFR, HIF-1α, c-Myc, WNT5A, and IDH3A. In summary, this study was able to identify a set of key genes significantly dysregulated during the development of GBM. Findings of this study have a major implication for the role of gene-environment interactions in the development of GBM, suggesting some of the key genes with potential to contribute to GBM.

Original languageEnglish (US)
Title of host publicationMODSIM 2011 - 19th International Congress on Modelling and Simulation - Sustaining Our Future
Subtitle of host publicationUnderstanding and Living with Uncertainty
Pages1037-1041
Number of pages5
StatePublished - 2011
Externally publishedYes
Event19th International Congress on Modelling and Simulation - Sustaining Our Future: Understanding and Living with Uncertainty, MODSIM2011 - Perth, WA, Australia
Duration: Dec 12 2011Dec 16 2011

Publication series

NameMODSIM 2011 - 19th International Congress on Modelling and Simulation - Sustaining Our Future: Understanding and Living with Uncertainty

Conference

Conference19th International Congress on Modelling and Simulation - Sustaining Our Future: Understanding and Living with Uncertainty, MODSIM2011
Country/TerritoryAustralia
CityPerth, WA
Period12/12/1112/16/11

Keywords

  • Bioinformatics
  • Gene-environment interactions
  • Glioblastoma

ASJC Scopus subject areas

  • Modeling and Simulation

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