CLONING OF THE 6Q27 TUMOR SUPPRESSOR GENE

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Deletions of chromosome 6q27 are associated at high frequency with various common tumor types including non-Hodgkin lymphoma (NHL;>20%), ovarian carcinoma (>70%), and breast carcinoma (approximately 50%). Loss of heterozygosity (LOH), radiation-hybrid mapping and cloning studies have identified a minimal region of loss within 6q27 common to all NHL cases and, within this region, a 60kb subregion containing the minimal regions of loss in breast and ovarian carcinoma. These associations suggest that 6q27 may contain a tumor suppressor gene (DOBL; deleted in ovarian, breast carcinoma and lymphoma) altered in multiple cancer types. The goal of this project is to identify the DOBL gene and to elucidate the role of its alterations in tumorigenesis. The following specific aims will be pursued: 1) Identification of the DOBL gene by mutation analysis of genes mapping within the 60 kb minimal deletion region in breast carcinoma cases carrying heterozygous deletions or wild-type 6q27 regions. 2. Screening ovarian carcinoma, NHL and other tumors for DOBL mutations in order to determine whether the same suppressor gene is involved in 6q27 deletions in different tumor types. 3. Characterization of the structure and pattern of expression of the DOBL gene product by determining it structural organization and homology to known proteins, its subcellular localization and its pattern of expression during development, tissue proliferation and differentiation. 4. Characterization of the biological function of the DOBL gene, including the analysis of its tumor suppressor activity in transfected cell lines in vitro, and its disruption in the mouse germ-line to determine its role on tissue-development and tumorigenesis in vivo.