Locating Novel Paget's Loci by Tumor Allelotyping

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DESCRIPTION (Verbatim from the Applicant): Paget's Disease of bone is the second most common metabolic disease of bone after osteoporosis. It results in rapid bone formation, altering the strength and shape of the bone. Predisposition to Paget's Disease has been linked in some families to chromosome 1 8q. However, recent evidence has shown that predisposition to Paget's Disease is genetically heterogeneous and that two or more loci must be involved in familial Paget's Disease predisposition. Osteosarcoma is a rare but serious complication of Paget's Disease. Our laboratory has identified an association between Paget's Disease and osteosarcoma. Analysis of both sporadic osteosarcomas and osteosarcomas from patients with Paget's Disease revealed that these tumors undergo tumor-specific loss of constitutional heterozygosity (LoH) in a region that is tightly linked to predisposition to Paget's Disease. This suggests that some of the genes that are involved in tumongenesis of osteosarcomas may also be involved in predisposition to Paget's Disease. There are three goals for this proposal. The first is to identify additional genes that predispose to Paget's Disease. We propose to take advantage of our unique collection of pagetic osteosarcomas to allelotype the entire genomes of normal, pagetoid bone, and tumor samples from patients with pagetic osteosarcoma to identify regions that may harbor novel tumor suppressor loci involved in either the pagetic or tumongenic process. These candidate regions can then be tested for linkage to familial Paget's Disease in chromosome 18q-unlinked Paget's families to determine if any of these novel tumor suppressor genes may represent additional Paget's predisposition loci. It is possible that we will not find genes involved in predisposition to Paget's Disease by this method. In this worst-case scenario, we will still realize our second goal, which is to characterize the genetic events that take place in pagetic osteosarcoma and to compare them to the genetic events that take place in sporadic osteosarcoma. This will allow us to determine whether these two diseases share common genetic origins. Further, by including pagetoid bone in our analysis we will be able to realize our third goal, which is to determine whether there are genes which act in a tumor suppressor-like fashion in the onset of sporadic Paget's Disease. Together, these analyses will allow us to examine both the predisposition to familial Paget's Disease, as well as to characterize the molecular genetics of pagetic osteosarcoma and sporadic Paget's Disease.