Circulating Repetitive Element RNAs as an Osteosarcoma Marker
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.
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 - June 1, 2020
Osteosarcoma is a malignant bone tumor of children, adolescents, and young adults. Some children who develop osteosarcoma have known high-risk factors, yet there are no tests for the potentially life-saving early detection of osteosarcoma prior to its clinical appearance. Our project aims to identify osteosarcoma biomarkers in the blood of such children before there are clinical signs of the malignancy, determine if such markers can be used to assess response to therapy, and understand how such markers are produced. The studies extend our past finding that extracellular vesicle (EV) preparations made from the blood of osteosarcoma patients have abnormally high levels of repetitive elements (REs) in RNA-sequencing analyses. This year, we used new bioinformatics tools to identify the most consistently over-represented REs, confirmed that they are increased in a “validation set” of osteosarcoma patients, revealed their DNA composition, and developed tests to quantitate their presence. Next year, we aim to 1) validate these findings in a larger number of patients, 2) assess whether the markers can be used to monitor response to therapy, 3a) determine whether EV-associated REs are over-produced in osteosarcoma cell cytoplasm, and 3b) determine how EV-associated REs associate with EV preparations. These studies are expected to provide insight into osteosarcoma pathogenesis and may provide a tool with which to monitor osteosarcoma development and therapy response.