Comparative DNA Microarray Analysis of Brain Tumors
Principal Investigator: Daniel Brat
Abstract: The following proposal is designed to provide the primary investigator, Daniel J. Brat, M.D., Ph.D., with necessary scientific experience and mentorship to allow a transition to an independent clinician scientist. Dr. Brat received his M.D. and Ph.D. degrees from Mayo Medical and Graduate Schools, and completed Anatomic Pathology and Neuropathology training at Johns Hopkins Hospital. His academic interests center on morphologic and molecular genetic investigations of primary brain tumors, both in terms of underlying mechanisms and classification. The goal of this proposal is to demonstrate a relationship between biologic behavior of brain tumors and their patterns of genetic alterations using comparative genomic hybridization in the format of DNA micro-arrays. Comprehensive tumor genotypes will be useful for determining pathways of genetic progression in distinct types of brain tumors, and for establishing patterns of genetic alterations that discriminate subsets of CNS neoplasms based on biologic behavior, response to therapy, and outcome. Genetic alterations that define certain gliomas are currently used to direct therapy: anaplastic oligodendrogliomas with 1p and 19q losses are sensitive to specific chemotherapy regimens. Distinct alterations among astrocytoma subtypes, including glioblastoma multiforme (GBM), have also been defined, but require further investigation in order to establish molecular subsets that may define behavior. Emerging micro-array technology offers the opportunity to define primary brain tumor genotypes comprehensively and precisely. Under the guidance of Erwin Van Meir, Ph.D., the first goal will be to demonstrate genetic alterations in the format of comparative genomic DNA arrays using a limited number of probes that are well characterized in adult GBMs. Once the experimental system has been validated, micro-arrays will be expanded to include a higher density of informational markers (200-300 loci). These will include gene families of significance in CNS tumorigenesis and markers from all chromosomes so that micro-arrays are useful for investigating patterns of genetic alterations in both glial and neuronal neoplasms, including those of childhood. Specialized DNA micro-arrays will be applied to biologically distinct brain tumors in order to define unique molecular genetic subgroups, and to gliomas from patients enrolled in clinical trials to determine if any patterns discriminate between tumors with regard to behavior, response to therapy, or clinical outcome.
Funding Period: 2001-12-15 - 2006-11-30
more information: NIH RePORT
- PTEN and hypoxia regulate tissue factor expression and plasma coagulation by glioblastomaYuan Rong
Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia, USA
Cancer Res 65:1406-13. 2005....
- The role of interleukin-8 and its receptors in gliomagenesis and tumoral angiogenesisDaniel J Brat
Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322, USA
Neuro Oncol 7:122-33. 2005..A precise definition of the mechanisms by which IL-8 exerts its proangiogenic functions requires further study for the development of effective IL-8-targeted therapies...
- 'Pseudopalisading' necrosis in glioblastoma: a familiar morphologic feature that links vascular pathology, hypoxia, and angiogenesisYuan Rong
Department of Pathology, Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30322, USA
J Neuropathol Exp Neurol 65:529-39. 2006....
- Early growth response gene-1 regulates hypoxia-induced expression of tissue factor in glioblastoma multiforme through hypoxia-inducible factor-1-independent mechanismsYuan Rong
Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School of Medicine, Atlanta, Georgia 30322, USA
Cancer Res 66:7067-74. 2006..We conclude that hypoxic up-regulation of tissue factor in glioblastoma multiforme cells depends largely on Egr-1 and is independent of HIF-1...
- Proteomic analysis of cerebrospinal fluid discriminates malignant and nonmalignant disease of the central nervous system and identifies specific protein markersFatima W Khwaja
Department of Neurosurgery, Emory University School of Medicine, Atlanta, GA 30322, USA
Proteomics 6:6277-87. 2006..3-13.7 kDa peak range in non-neoplastic CSF and was most prominent in inflammatory conditions. Our approach provides a rational basis for identifying biomarkers that could be used for detection, diagnosis, and monitoring of CNS diseases...
- Congenital glioblastoma: a clinicopathologic and genetic analysisDaniel J Brat
Departments of Pathology and Laboratory Medicine and Winship Cancer Institute, Emory University School of Medicine, 1364 Clifton Road NE, Atlanta, GA 30322, USA
Brain Pathol 17:276-81. 2007..Nonetheless, the strong nuclear expression of p53 in these and other pediatric GBMs could indicate that p53 dysregulation is important to tumorigenesis...