Our general goal is to identify the function of tumor suppressor genes with relevance for disorders of the nervous system (MEN1, VHL, NF2) as well as to pursue genetic and functional studies of these and other tumor-related genes in glial tumors of the CNS. Beyond this, we are interested in moving one step beyond molecular genetics to identify ways in which the pathogenesis of tumors may be studied and eventually used for therapy. Potential important questions to pursue include: What is (are) the genetic event(s) which occur during tumorigenesis? For example, current work in our lab has shown that loss of heterozygosity (LOH) in VHL- and MEN1-associated tumors may be related to a direct effect of the inherited, mutated allele on the second, wild-type allele. Conversely, when a deletion occurs as the primary event (germline mutation), we have observed that the wild-type allele has become mutated in most cases. These studies are currently being confirmed in larger studies with more tumors. Our long-range goal is to elucidate the mechanism that underlies this phenomenon, both to see if it is a common event with other tumor suppressor genes and if it is an even more widespread event in tumorigenesis. Pathogenesis of MEN2-associated neuroendocrine tumors. Work in our lab has recently shown that there may be an oncogene-related corollary to Knudson's traditional tumor suppressor hypothesis. In Knudson's theory, one observes ?two hits?, with one inherited mutation allele and a deletion as a second ?hit? in the second, wild-type allele, which leads to development of tumors. Previously, we have cloned the gene responsible for papillary renal cell carcinoma, the c-met oncogene. In this tumor, we have identified a novel mechanism for tumorigenesis, in which the ?first hit? is an inherited mutation in the c-met oncogene and the ?second hit? is duplication of the mutated allele (whereby duplication causes trisomy of the chromosome) which leads to a dominant effect and the development of tumor. This mechanism is novel and may underlie tumorigenesis in other types of tumors. Recently, we identified that similar mechanisms are also applicable to other oncogenes, e.g. c-ret mutant allele duplication as an early event in MEN-2-associated pheochromocytoma. In addition, we identified other possible events leading to imbalance of mutant allele representation including wild-type allele deletion and in-situ mutant gene amplification. Pathogenesis of malignant glial tumors. Several years ago SNB created a primate model for glioma tumorigenesis using a radiation dose that is sufficient to initiate intracerebral tumors, but low enough to allow long term survival. Morphologic analysis revealed the tumors to be de novo glioblastomas, sometimes occurring multifocally. Brain and tumor tissue from these monkeys may provide clues to a better understanding of human glioma tumorigenesis (Lonser et al., J. Neurosurg., in press). In particular, atypical glial cells were identified in characteristic topographic areas in at least one brain that was unaffected by tumor. Ware in the process of further neuropathologic evaluation of these radiation-induced gliomas and ?normal? brain tissue and the procurement of tissues for further laboratory studies including morphology, immunohistochemistry and molecular genetic studies. Pathogenesis of VHL-associated hemangioblastomas. We have completed an extensive morphologic analysis of an abundance of CNS and other tissue samples obtained at autopsy from patients with VHL disease. This approach provided a detailed spectrum of tumorigenesis illustrating the earliest precursor lesions, as well as large-sized hemangioblastomas. The results indicate that that early hemangioblastoma tumorigenesis in VHL disease is restricted to specific anatomic areas in spinal cord and cerebellum. The phenotype of early ?precursor? lesions is markedly different from that of larger tumorresected at surgery and may provide important clues about tumor mechanisms of tumor progression. The lesions were further analyzed using specialized techniques to compare early lesions with clinically progredient hemangioblastoma (manuscript in preparation). Further clues were obtained by detailed studies of surgically removed, progressive hemangioblastomas that revealed more intense activation of the hif-1 alpha signal transduction pathway and evidence for autocrine pathway activations (manuscript in preparation). During these studies, we obtained additional strong evidence for a primary developmental origin of hemangioblastoma which may also broaden our understanding of other VHL-related tumors. Work is in progress to solidify this concept. Further collaborations with other branches: Identification of HHV6 viral protein in epilepsy brain tissue via a new dissection technology (Steve Jacobson, NINDS) Detailed morphologic analysis of palatal myoclonus associated with olivary hypertrophy (Mark Hallett, NINDS) Differentiation spectrum of bone marrow derived stem cells (Howard Fine, NIINDS/NCI) Detailed myeloarchitectonic analysis of brain tissue using up to date MRI technology (Alan Koretsky, NINDS) 2D protein analysis for protein expression profiling using neurons derived from patients with lipid storage diseases (Roscoe Brady, NINDS) Genetic analysis of NF2-associated retinal and optic nerve lesions (Chi-Chao Chan, NEI)

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National Institute of Neurological Disorders and Stroke (NINDS)
Intramural Research (Z01)
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