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 characterized by rapid bone remodeling resulting in abnormal bone formation. It is the second most common metabolic bone disease after osteoporosis, affecting 3%-5% of subjects aged >40 years. Recent evidence suggests that predisposition to Paget disease may have a genetic component. Genetic linkage analysis of families with multigenerational Paget disease shows linkage to a region of chromosome 18q near the polymorphic locus D18S42. Approximately 1% of Paget patients develop osteosarcoma, 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 occurring after age 60 years. Our analysis of tumor-specific loss of constitutional heterozygosity (LOH) in 96 sporadic osteosarcomas has identified 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 osteosarcomas from patients with Paget disease revealed that these tumors also undergo LOH in this region. These findings suggest that the association between Paget disease and osteosarcoma is the result of a single gene or two tightly linked genes on chromosome 18.
Fels Institute for Cancer Research and Molecular Biology, Temple University School of Medicine, Philadelphia, PA 19140, USA.
M J
MJ
Nellissery
S S
SS
Padalecki
Z
Z
Brkanac
F R
FR
Singer
G D
GD
Roodman
K K
KK
Unni
R J
RJ
Leach
M F
MF
Hansen
D000328:Adult; D001859:Bone Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D002874:Chromosome Mapping; D002887:Chromosomes, Human, Pair 18; D002893:Chromosomes, Human, Pair 3; D016147:Genes, Tumor Suppressor; D008040:Genetic Linkage; D005819:Genetic Markers; D006801:Humans; D019656:Loss of Heterozygosity; D008875:Middle Aged; D010001:Osteitis Deformans / Q000235:genetics*; D012516:Osteosarcoma / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D010375:Pedigree; D012307:Risk Factors
D005819:Genetic Markers