Characterization of the Osteosarcoma Genome

Division Of Basic Sciences - Nci

Investigators

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Abstract

Osteosarcoma remains a serious challenge with significant unmet clinical needs. Outcomes remain bleak for many patients, particularly those with metastatic disease at diagnosis or with early recurrence. Remarkably, most osteosarcomas initially respond well to chemotherapy, but tend to relapse with drug resistant disease, and are seldom cured once resistant clones emerge. Unlike some sarcomas that have targetable driver mutations, osteosarcomas are characterized by extreme genome instability and dysregulation of cell cycle genes but do not frequently carry a druggable driver gene. Comprehensive genome characterization is difficult in humans, as neoadjuvant therapy is typically administered leaving little viable tumor in the surgical specimen. This is not a problem in canine osteosarcomas, now known to be quite similar to human tumors in many respects. One similarity is the occurrence of primary tumors in limb bones. Unlike humans, dogs are initially treated by amputation of the affected limb. The opens up the possibility to study the clonal complexity of the tumor. We are using long and short read sequencing to address this question. By dissecting geographically different regions of the bone, we can discern regional differences to provide insights into the complex evolution of these tumors. The canine system also appears to be a useful surrogate for human osteosarcoma in studies of the extracellular matrix and the immune microenvironment.