Title

Molecular characterization of head and neck osteosarcoma

Date of Completion

January 2005

Degree

Ph.D.

Abstract

Osteosarcoma is the most common primary tumor of bone and the third most common malignancy in adolescents. Osteosarcoma of all sites accounts for approximately 20% of all malignant tumors of bone and approximately 7,500 new cases annually in the United States. Although a majority of osteosarcomas occur in the long bones of the skeleton, 6-13% of all osteosarcomas occur in the head and neck. Evidence from the differences in the degree of cellular atypia, the frequency of local versus distant metastases, the time until metastases, and the median age of onset, suggests that primary osteosarcoma of the long bones and primary osteosarcoma of the head and neck represent biologically discrete diseases. To test this hypothesis, genome-wide allelotype analysis was conducted to identify regions of tumor-specific Constitutional Loss of Heterozygosity (LoH) as well as the evaluation of the expression patterns of genes implicated in appendicular osteosarcoma tumorigenesis. For the allelotype analysis, 18 head and neck osteosarcoma tumors were used to study the allelic patterns of 66 microsatellite markers distributed throughout the genome. The overall frequency of LoH in the head and neck osteosarcoma was 53% with 30 chromosomal arms undergoing consistent LoH. Of these 11 chromosomal regions showed significant differences in frequency of LoH from those seen in long bone osteosarcomas (pavg = 0.02). Deletions of genomic regions involving tumor suppressor genes are thought to be important for the initiation and progression of malignancy. Therefore, the difference in the frequency and distribution pattern of LoH for head and neck osteosarcoma from that of long bone osteosarcoma suggests that the tumor pathogenesis is also distinct. Expression patterns of candidate genes previously implicated in appendicular osteosarcoma tumorigenesis revealed that the expression patterns of some of these genes differed in head and neck osteosarcomas from those observed in the appendicular osteosarcomas. These results support the hypothesis that the mechanism of tumorigenesis in these two forms of osteosarcoma is distinct and that primary head and neck osteosarcoma may be a separate disease from appendicular skeletal osteosarcoma.