Objective: Based on degree of cellular atypia, frequency of local versus distant metastases, time until metastases, and median age of onset, there is strong evidence that osteosarcoma of the craniofacial bones and osteosarcomas of the appendicular skeleton represent separate and distinct diseases. This may be a result of different developmental pathways by which the bones of the appendicular and craniofacial skeleton arise; the craniofacial bones arise from cranial neural crest cells while the appendicular skeleton arises from mesenchymally-derived cells. Methods: We used frequency of allelic loss (allelotype) analysis to compare patterns of tumor-specific loss of constitutional heterozygosity (LoH) from primary craniofacial and appendicular osteosarcomas. Results:We found that craniofacial osteosarcomas experience a significantly greater overall frequency of LoH than primary appendicular osteosarcomas (LoHavg=53% versus 30%; p < 0.0004). Analysis of LoH on individual chromosomal arms identified 12 chromosomal arms with significantly different frequencies of LoH (p <=0.05). Six chromosomal arms showed significantly greater LoH in craniofacial osteosarcoma while the six chromosomal arms showed a significantly greater frequency of LoH in appendicular osteosarcomas (p <=0.05).Conclusion:Our discovery suggested two things: first, that chromosomal instability leading to increased LoH plays a significant role in the onset or progression of this disease. Second, since LoH is associated with the presence of tumor suppressor genes, the variation in frequency of LoH at specific chromosomal locations likely represents alterations in distinct sets of tumor suppressor genes, supporting the notion that there are divergent tumorigenic pathways between craniofacial and long bone osteosarcomas.

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