Our general goal is to identify the function of tumor suppressor genes with relevance for disorders of the nervous system (MEN 1, VHL, NF-2) 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 need to be confirmed in larger studies with more tumor types. Our long-range goal is to elucidate the mechanism that underlies this phenomenon, both to see if it is common event with other tumor suppressor genes and if it is an even more widespread event in tumorigenesis. Oncogenesis in inherited cancer syndromes related to tumor oncogenes. Work in our lab has recently shown that there may be a 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.) Recently, 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 the tumor. This mechanism is novel and may underlie tumorigenesis in other types of tumors. Most 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. Studies of pathogenetic events in radiation-induced glioma in monkey. Several years ago SNB created a primate model for glioma tumorigenesis radiation dose that is sufficient to initiate intracerebral gliomas, but low enough to allow long term survival. We are in the process of neuropathologic evaluation of these radiation-induced gliomas and the procurement of tissues for further laboratory studies including morphology, immunohistochemistry and molecular genetic studies. The studies are predicted to give new insight into the pathogenesis of gliomas and glioma invasion of the brain. Pathogenesis of VHL-associated hemangioblatomas. We are in the process of an extensive morphologic analysis of an abundance of CNS and other tissue samples obtained at autopsy from patients with VHL disease. This approach provides a detailed spectrum of tumorigenesis illustrating the earliest precursor lesions, as well as large-sized hemangioblastomas. The obtained material is used to address the following questions: At what developmental stage does the *second hit* occur? What morphologic stages of tumorigenesis can be defined, and are these stages associated with functional/genetic alterations? Only certain tissues are affected in hereditary tumor syndromes. Through this study, we can investigate whether secondary genetic changes are restricted to these tissues or whether all tissues are similarly affected by *second hits*, but are not tumorigenetic due to environmental factors.

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