Tumor suppressor genes define a broad class of genetic information lost or inactivated during human tumor development. Despite the great interest in the identification of these genes, only a handful have been defined. Most of these genes were isolated solely on their location as determined by cytogenetics and allelotyping, making assessments of their functions a difficult task. Furthermore, these positional studies have failed to detect all tumor suppressor genes. We have taken a different approach to the identification of these pediatric cancers. Childhood malignancies offer an excellent model system for cancer genetics because of the short period of patient exposure to environmental influences. Many of the clearest examples of cytogenetic abnormalities come from studies of pediatric cancers. In our initial studies, we have shown the presence of at least three different tumor suppressor genes on human chromosome 11 and potentially an additional gene on chromosome 17. In this competitive renewal, we plan to localize these genes to specific sites on these chromosomes by generating smaller fragments for microcell transfer. Once we have identified fragments which contain these tumor suppressor genes, we will use them to identify other types of pediatric cancers where they may be inactivated. We intend to define the lower limits of the microcell transfer technique by isolating the smallest fragments of chromosome 11 retaining functional tumor suppressor genes. We will develop a long range physical map of region surrounding the tumor suppressor genes by screening our panel of chromosome 11 fragments with new and existing DNA markers. We will use the smallest fragment retaining the tumor suppress activity as the source for these new molecular probes. We will also screen primary tumor material with any DNA markers closely linked to the tumor suppressor gene to search for potential deletions or rearrangements. Finally, we will characterize a tumor suppressor activity on chromosome 17 for peripheral neuroepitheliomas. The availability of new molecular probes closely linked to these genes will provide the necessary tools for their cloning. Their ultimate isolation will lead to new insights into the control of cellular growth and differentiation in general as well the development of new diagnostic markers and treatment modalities for these neoplasia.
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