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.
Showing the most recent 10 out of 17 publications
