Common mechanisms of osteosarcoma and Paget's disease.
One of the most serious complications of Paget's disease is a significant increase in the incidence of osteosarcoma. Approximately 1% of Paget's patients develop osteosarcoma, an increase in risk that is several thousand-fold higher than the general population. This risk contributes significantly to the mortality and morbidity of Paget's disease patients. We examined several cases of pagetic and sporadic osteosarcoma for tumor-specific loss of constitutional heterozygosity (LoH) on chromosome 18q. Our analysis found that both pagetic and sporadic osteosarcoma tumors showed LoH for all or part of the distal portion of chromosome 18q. The pattern of LoH in both types of tumors identified a region between loci D18S60 and D18S42 that must contain the putative tumor suppressor locus. This region is tightly linked to familial Paget disease and familial expansile osteolysis (FEO). Our hypothesis is that the predisposition locus for Paget's disease and the tumor suppressor locus for osteosarcoma are either the same gene or that osteosarcoma in Paget's disease represents a deletion affecting two adjacent genes. In either model, localization of the osteosarcoma tumor suppressor gene would be of benefit in the eventual isolation of the predisposition locus for Paget's disease. We have begun to isolate and test candidate genes from within the region defined by both the familial Paget's disease families and the minimal region of LoH in osteosarcomas for evidence that one or more of them is responsible for predisposition to Paget's disease and/or osteosarcoma.
Hansen
M F
MF
Center for Molecular Medicine, University of Connecticut Health Center, Farmington, CT 06030, USA.
Nellissery
M J
MJ
Bhatia
P
P
D001859:Bone Neoplasms / Q000209:etiology* / Q000235:genetics; D002874:Chromosome Mapping; D006801:Humans; D010001:Osteitis Deformans / Q000150:complications* / Q000235:genetics; D012516:Osteosarcoma / Q000209:etiology* / Q000235:genetics