Circulating Repetitive Element RNAs as an Osteosarcoma Marker
Background: Osteosarcoma is a highly-malignant bone tumor in children, adolescents and young adults. The tumors form in ~5 in one million individuals per year, ages 0-19, giving an overall risk of ~1/10,000 over the first 20 years. Some children who develop osteosarcoma have a genetic predisposition, whereas others have a predisposition based on their prior exposure to certain cancer treatments. Regardless of predisposing factors, osteosarcomas often fail to respond to available therapies or rapidly relapse. For these reasons, biomarkers are needed to both detect early osteosarcoma tumors before they progress to larger and more therapy-resistant forms and to monitor the tumor’s response to therapy. We identified a novel biomarker that is elevated in the blood of each of 12 patients with newly-diagnosed osteosarcoma compared to healthy individuals. Specifically, we found that so-called repetitive element RNAs are significantly increased in the small bits of tumor cells, called extracellular vesicles (EVs), which circulate in the blood of osteosarcoma patients.
Project Goal: This study seeks to develop a test to identify these osteosarcoma-related repetitive element RNAs in predisposed children before osteosarcomas develop, to test whether such EVs can monitor response to therapy and relapse and to identify what has gone wrong in the tumor cells that enables their increased production. These studies are expected to lead to a new osteosarcoma marker test and possibly new therapeutic approaches that may substantially improve outcomes for osteosarcoma patients.
Project Update 2021: In the first year of this project, we identified consistently over-represented REs in two cohorts of treatment-naïve osteosarcoma patients, revealed their DNA composition, and developed tests to quantitate their presence. In the second year, we 1) found that RE DNA abundance was increased in small cohort of relapsed osteosarcoma patients; 2) obtained approvals to obtain treatment-naïve osteosarcoma patient serum and plasma samples with which to confirm initial findings, define the optimal sample source, and examine levels longitudinally in a large multi-center osteosarcoma clinical trial; 3) found that RE DNAs co-purified with but were not tightly associated with exosomal extracellular vesicles; and 4) demonstrated that HSATII RE DNA is detected in osteosarcoma cell cytoplasm and the surrounding culture media and that these extranuclear species increased in response to DNA damaging agents. These findings provide a foundation with which to further assess and potentially implement a RE DNA test for osteosarcoma early detection as well as for therapy response and relapse monitoring.
