EVIDENCE FOR A NOVEL OSTEOSARCOMA TUMOR-SUPPRESSOR GENE IN THE CHROMOSOME-18 REGION GENETICALLY LINKED WITH PAGET-DISEASE OF BONE

Paget disease of bone, or ''osteitis deformans,'' is a bone disorder c haracterized by rapid bone remodeling resulting in abnormal bone forma tion. It is the second most common metabolic bone disease after osteop orosis, affecting 3%-5% of subjects aged >40 years. Recent evidence su ggests that predisposition to Paget disease may have a genetic compone nt. Genetic linkage analysis of families with multigenerational Paget disease shows linkage to a region of chromosome 18q near the polymorph ic locus D18S42. Approximately 1% of Paget patients develop osteosarco ma, which represents an increase in risk that is several thousandfold over that of the general population. Osteosarcoma in Paget patients is the underlying basis for a significant fraction of osteosarcomas occu rring after age 60 years. Our analysis of tumor-specific loss of const itutional heterozygosity (LOH) in 96 sporadic osteosarcomas has identi fied a putative tumor-suppressor locus that maps to chromosome 18q. We have localized this tumor-suppressor locus between D18S60 and D18S42, a region tightly linked to familial Paget disease. Analysis of osteos arcomas from patients with Paget disease revealed that these tumors al so undergo LOH in this region. These findings suggest that the associa tion between Paget disease and osteosarcoma is the result of a single gene or two tightly linked genes on chromosome 18.