The short arm of chromosome 8 is a site of allele loss in a variety of cancers of epithelial origin, and we have postulated the existence of a tumor suppressor gene (TSG) on this chromosome; there is clinical evidence to suggest that this TSG is involved in tumor progression rather than transformation, and we will take advantage of this activity to develop a biologic assay for the gene. Deletion mapping by us and by others has demonstrated that there exist two distinct Sites of loss of heterozygosity in colorectal cancer; here we propose to study the distal region at 8p22 because it has been implicated in a wide variety of tumor types, including prostate, lung, breast, and colorectal. Overall, we plan to take a positional cloning approach, making use of biologic materials which are relevant to the study. Our studies will span a range of tumor types, but we will continue to focus on colorectal cancer because of our unique materials-colon cancer cell lines which we are establishing-that will facilitate the search for the gene. We have joined forces with Dr. Rob Bookstein, who has made available to us a YAC contig and information on a homozygous deletion in prostate cancer. We are also working with Dr. Carrie Rinker-Schaeffer, who is experienced in a metastasis suppression assay in prostate cancer, that we will apply to our gene.
Our specific aims are: (1) to refine the localization of the 8p22 deletion region, and prepare a complete P1 contig; (2) to develop a biologic assay for the 8p TSG based on suppression of growth or metastases in the Dunning prostate cancer cell lines; (3) to isolate and test candidate genes from the deletion region, using genetic methods as well as biological assays; (4) to begin to characterize this new TSG biologically, including cDNA sequencing and genomic mapping, and mutational analysis of tumors and colon cancer cell lines. This gene is implicated in a number of common cancers such as lung, colon, prostate, and breast; our identification of the gene will be important to understanding the biology of these tumors, which together comprise the overwhelming majority of all cancers in the US today.
