Identification and functional studies of acquired genetic aberrations in bone tumors

The most common primary malignant bone tumor is osteosarcoma. This disease has a bimodal age distribution with one peak during the adolescent growth spurt and another peak in older adults. Today, it is not known whether osteosarcoma is uniform disease regardless of the age of the patient or if tumors in young and old patients represent distinct diseases. Overall, osteosarcoma is a disease with high mortality despite the fact that the affected patients receive an aggressive treatment with many side effects. Most patients are given chemotherapy followed by major surgery to remove the primary tumor. If the disease spreads, excision of lung metastases and second line chemotherapy may be considered. Since the late 1980s, the 5–year event free survival has stalled at less than 70% for patients with localized tumor and about 20% for patients with metastatic or relapsed disease. Hence, clinical outcomes and therapeutic strategies have remained virtually unchanged for decades. The purpose of the project is to understand why osteosarcoma is such a difficult disease to treat and ultimately to find new therapeutic targets. The specific aims are to:

1. Identify genetic subgroups of osteosarcoma by analyzing global gene expression levels and correlate these subgroups with clinical information. RNAseq data is now available for this purpose and is pending analysis.
2. Evaluate whether osteosarcoma and other bone tumors harbor gene fusions of importance for tumor development and progression. Both RNAseq and mate-pair whole genome sequencing data have been generated for osteosarcoma and osteoblastoma samples and are currently under analysis.
3. Identify genetic aberrations responsible for the development of benign osteoblastoma and low–grade osteosarcoma and compare these changes with the ones found in high–grade osteosarcoma
4. Functionally evaluate genes that are identified from any of the above three aims