Telomere Maintenance Mechanisms in Human Osteosarcoma

点击翻译按钮获取中文摘要

DESCRIPTION (provided by applicant): Osteosarcoma is the most common primary bone tumor of children and adolescents. Despite significant treatment advances over the past 30 years, approximately 30% of patients with localized disease and 60% of patients with metastatic disease do not survive. Novel prognostic markers and therapeutic targets are needed to improve the outcomes of patients with osteosarcoma. Telomeres are nucleoprotein structures that cap chromosome ends. With each round of replication, telomeres erode due to the inability of DNA polymerases to replicate the very ends of DNA. When telomeres become critically short, cellular senescence or apoptosis are induced. A hallmark of cancer cells is that they have unlimited proliferative potential. To achieve this, they must develop mechanisms to counteract telomere shortening. Most human cancers activate the enzyme telomerase to maintain telomeres, but a minority of cancers use a poorly defined mechanism called "alternative lengthening of telomeres," or "ALT." Osteosarcoma is dissimilar from most human cancers in that osteosarcomas commonly use the ALT mechanism. Laboratory studies have shown that compared to ALT, telomerase expression is associated with increased tumorigenicity and metastasis. This raises the possibility that the telomerase-dependent osteosarcomas are more clinically aggressive than their ALT-dependent counterparts. In collaboration with the Children's Oncology Group (COG), this study will evaluate the prognostic significance of telomerase expression in patients with non-metastatic osteosarcoma. In addition, this study will take advantage of the heterogeneity of telomere maintenance mechanisms in human osteosarcoma to identify novel biomarkers for ALT.