My laboratory is interested in the discovery and analysis of genes involved in the development of the bone tumor osteosarcoma. Osteosarcoma is the most common primary tumor of bone. Osteosarcoma appears during the first three decades of life particularly during times of bone growth. The survival rate of patients with osteogenic sarcoma has greatly improved with the institution of a multidisciplinary approach that combines multi-agent chemotherapy and limb-sparing surgery. Presently, 80% of those patients who do not have distant metastases at presentation will become long-term survivors. Unfortunately, this means that approximately 20% of patients who do not have metastases at diagnosis do not survive and it is these patients who are difficult to identify at diagnosis and whose tumors do not behave as predicted by their histopathological classification that are in the greatest need for additional clinically relevant markers and who can be most helped by molecular analysis. While steady progress has been made in the identification of genetic alterations and prognostic factors in osteosarcoma, to date, the most powerful predictors of outcome have remained the ability to detect metastatic disease at diagnosis and the histopathologic response of the tumor to preoperative chemotherapy. However, a better understanding of the genetic changes that occur in osteosarcoma could offer these patients the potential for more meaningful molecular diagnosis and a more accurate prediction of their cancer risk as well as the hope of developing novel therapies.

Osteosarcoma is also a rare complication of Paget's Disease of Bone. Paget's Disease of Bone is the second most common metabolic disease of bone after osteoporosis and is a condition in which rapid bone formation occurs, altering the strength and shape of the bone. Predisposition to Paget's Disease has been linked in some families to chromosome 18q. 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. 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 the region of chromosome 18q that is tightly linked to familial predisposition to Paget's Disease. This suggests that at least some of the genes that are involved in tumorigenesis of osteosarcomas may also be involved in predisposition to Paget's Disease. We are now scanning DNA from normal and tumor samples from patients with pagetic osteosarcoma to identify additional regions that may harbor novel tumor suppressor loci involved in the tumorigenic process associated with pagetic osteosarcoma. 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. Together these analyses will allow us to examine the predisposition to familial Paget's Disease and to characterize the molecular genetics of pagetic osteosarcoma and sporadic Paget's Disease.