Studies to determine the etiology of osteosarcoma involve epidemiologic and 
environmental factors and genetic impairments. Factors related to patient 
characteristics include age, gender, ethnicity, growth and height, genetic and 
familial factors, and preexisting bone abnormalities. Rapidly proliferating 
cells may be particularly susceptible to oncogenic agents and mitotic errors 
which lead to neoplastic transformation. Genetic aberrations that accompany 
osteosarcoma have received increasing recognition as an important factor in its 
etiology. Osteosarcoma tumor cells exhibit karyotypes with a high degree of 
complexity which has made it difficult to determine whether any recurrent 
chromosomal aberrations characterize osteosarcoma. Although extremely rare, 
osteosarcoma has occasionally been observed in several members of the same 
family. No other clinical abnormalities in the proband or the affected members 
were reported. Pathologic examination of the tumors revealed no unusual 
features. Genetic testing was not available in most of these reports. The 
patients generally responded to conventional therapy. A genetic predisposition 
to osteosarcoma is found in patients with hereditary retinoblastoma, 
characterized by mutation of the retinoblastoma gene RB1 on chromosome 13q14. 
The Rothmund-Thomson syndrome is an autosomal recessive disorder with a 
heterogeneous clinical profile. Patients may have a few or multiple clinical 
features including skin rash, small stature, skeletal dysplasias, sparse or 
absent scalp hair, eyebrows or eyelashes, juvenile cataracts, and 
gastrointestinal disturbance including chronic emesis and diarrhea; its 
molecular basis is the mutation in the RECQL4 gene in a subset of cases. The 
Li-Fraumeni syndrome is an autosomal dominant disorder characterized by a high 
risk of developing osteosarcoma and has been found in up to 3% of children with 
osteosarcoma. It is associated with a germline mutation of the p53, a suppressor 
gene. The following three criteria must be met for a diagnosis of Li-Fraumeni 
syndrome: (1) A proband diagnosed with sarcoma when younger than 45 years; (2) A 
first-degree relative with any cancer diagnosed when younger than 45 years; (3) 
Another first- or second-degree relative of the same genetic lineage with any 
cancer diagnosed when younger than 45 years or sarcoma diagnosed at any age. A 
second recessive p53 oncogene on chromosome 17p13.1 may also play a role in the 
development and progression of osteosarcoma. Osteosarcoma has also been 
associated with solitary or multiple osteochondroma, solitary enchondroma or 
enchondromatosis (Ollier's disease), multiple hereditary exostoses, fibrous 
dysplasia, chronic osteomyelitis, sites of bone infarcts, sites of metallic 
prostheses and sites of prior internal fixation. Ionizing radiation is a 
well-documented etiologic factor. Osteosarcoma has also been associated with the 
use of intravenous radium and Thorotrast. Exposure to alkylating agents may also 
contribute to its development ,and it is apparently independent of the 
administration of radiotherapy.