Osteogenic Sarcoma
A number sign (#) is used with this entry because of evidence that many instances of osteogenic sarcoma occur in association with retinoblastoma (RB; 180200), which is caused by mutation in the RB1 gene (614041) on chromosome 13q14.
Osteosarcoma occurs frequently in Paget disease of bone, which can be caused by mutation in the TNFRSF11A gene on chromosome 18q22. Mutation in another gene on chromosome 18q may be mutated in cases of osteosarcoma. Osteosarcoma is a feature of Li-Fraumeni syndrome-1 (LFS1; 151623), caused by mutation in the TP53 gene (191170), and of Li-Fraumeni syndrome-2 (LFS2; 609265), caused by mutation in the CHEK2 gene (604373). Sporadic osteosarcoma has also been associated with mutations in the CHEK2 gene (604373.0005).
Osteosarcoma is a component of the acronymically designated OSLAM syndrome (165660).
Clinical FeaturesHarmon and Morton (1966) reported osteogenic sarcoma in 4 sibs, with onset at 11, 15, 20, and 22 years. Epstein et al. (1970) observed osteogenic sarcoma in a father and daughter. See chondrosarcoma (215300).
Goorin et al. (1985) stated that 16 sets of sibs with osteosarcoma had been identified.
The demonstration of evidence of immune response (lysis of radiolabeled tumor cells by donor lymphocytes) in household contacts of patients with osteosarcoma (Levin et al., 1974) suggested that the familial aggregation may be due to a transmitted agent.
CytogeneticsGilman et al. (1985) described osteosarcoma developing in 2 prepubertal American Indian sisters at age 8 and 12 years. Rearrangements involving chromosomes 13 and 14 were found in both the surviving sister and the mother. The mother had a typical Robertsonian translocation of 13 and 14. The daughter had a rearrangement of ambiguous nature.
MappingDryja et al. (1986) provided evidence that some human osteosarcomas arise subsequent to the development of homozygosity at loci on the long arm of chromosome 13. They proposed that this is the same locus as the retinoblastoma locus. In all 11 cases of osteosarcoma, Scheffer et al. (1991) found loss of heterozygosity of both chromosomes 13 and 17.
Association with Retinoblastoma
Survivors of the bilateral form of retinoblastoma (RB; 180200) have an increased risk of osteosarcoma. Survivors of unilateral retinoblastoma show the same likelihood of developing osteosarcoma as the general population. It is plausible to think that much of sporadic osteosarcoma is due to homozygosity (or hemizygosity) for a mutation at the RB1 locus on chromosome 13 (Dryja et al., 1986).
Chauveinc et al. (2001) reviewed retinoblastoma survivors who subsequently developed osteosarcoma. They found that osteosarcomas occurred 1.2 years earlier inside than outside the radiation field in patients who had undergone external beam irradiation. Also, the latency between radiotherapy and osteosarcoma was 1.3 years shorter inside than outside the radiation field. Bimodal distribution of latency periods was observed for osteosarcomas arising inside but not outside the radiation field: 40% occurred after a short latency, while the latency for the remaining 60% was comparable to that of osteosarcoma arising outside the radiation field. The authors suggested that different mechanisms may be involved in the radiocarcinogenesis. They hypothesized that a radiation-induced mutation of the second RB1 allele may be the cause of osteosarcomas occurring after a short delay, while other genes may be responsible for osteosarcomas occurring after a longer delay.
Association with Paget Disease of Bone
Paget disease of bone (PDB; see 167250), or 'osteitis deformans,' is a bone disorder characterized by rapid bone remodeling resulting in abnormal bone formation. Approximately 1% of Paget patients develop osteosarcoma, which represents an increase in risk that is several thousand-fold over that of the general population. Osteosarcoma in Paget disease patients is the underlying basis for a substantial fraction of osteosarcomas occurring after age 60 years. Nellissery et al. (1998) identified, by analysis of tumor-specific loss of constitutional heterozygosity (LOH) in 96 sporadic osteosarcomas, a putative osteosarcoma tumor-suppressor locus that mapped to 18q. They 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 showed that these tumors also undergo LOH in this region. The findings suggested that the association between Paget disease and osteosarcoma is the result of a single gene or 2 tightly linked genes on chromosome 18.
Molecular GeneticsSadikovic et al. (2009) performed integrative whole-genome analysis of DNA copy number, promoter methylation, and gene expression using 10 pediatric osteosarcoma tissue samples. Hypomethylation, copy number gain, and overexpression were identified for the histone cluster 2 genes (see 142750) on chromosome 1q21.1-q21.3. They also found loss of chromosome 8p21.3-p21.2 and underexpression of DOCK5 (616904), TNFRSF10A (603611), and TNFRSF10D (603614) genes, as well as copy number gain of chromosome 6p21.1-p12.3 and amplification-related overexpression of RUNX2 (600211). Amplification and overexpression of RUNX2 could disrupt G2/M cell cycle checkpoints, and downstream osteosarcoma-specific changes, such as failure of bone differentiation and genomic polyploidization. Failure of DOCK5 signaling, together with p53 (191170) and TNFRSF10A/D-related cell cycle and death pathways, may play a critical role in abrogating apoptosis. Sadikovic et al. (2009) hypothesized that the RUNX2 interactome may be constitutively activated in osteosarcoma, and that the downstream intracellular pathways may be associated with the regulation of osteoblast differentiation and control of cell cycle and apoptosis in osteosarcoma.
Animal ModelKhanna et al. (2000) developed a murine model of osteosarcoma characterized by tumor growth at appendicular sites, a period of minimal residual disease, spontaneous pulmonary metastasis, and model variants that differ in metastatic potential. The model was developed from a cell line, K12, originating from a spontaneous BALB/c osteogenic sarcoma, and a clonally related cell line, K7M2. Within the model, the K7M2 cell line is aggressive and highly metastatic, whereas the K12 cell line is less aggressive with infrequent pulmonary metastases. Khanna et al. (2001) used cDNA microarray expression profiling to compare gene expression between these cell lines. They showed that ezrin (123900) had a 3-fold overexpression in the K7M2 versus the K12 cell line. The relevance of ezrin in human osteosarcoma was supported by Northern blot analysis that demonstrated its expression in 5 of 5 human osteosarcoma cell lines.
By imaging metastatic osteosarcoma cells in the lungs of mice, Khanna et al. (2004) demonstrated that ezrin expression provides an early survival advantage for cancer cells that reach the lung. AKT (164730) and MAPK3 (601795) phosphorylation and activity were reduced when ezrin was suppressed. Ezrin-mediated early metastatic survival was partially dependent on the activation of MAPK but not AKT. To define the relevance of ezrin in the biology of metastasis beyond the founding mouse model, Khanna et al. (2004) examined ezrin expression in dogs that naturally developed osteosarcoma. High ezrin expression in dog tumors was associated with early development of metastases. Consistent with these data, Khanna et al. (2004) found a significant association between high ezrin expression and poor outcome in pediatric osteosarcoma patients.