Abstract
Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. Despite that high-risk factors have been identified, no test for early detection is available. This study aimed to identify circulating nucleic acid sequences associated with serum extracellular vesicle (EV) preparations at the time of OS diagnosis, as a step towards an OS early detection assay. Sequencing of small nucleic acids extracted from serum EV preparations revealed increased representation of diverse repetitive element sequences in OS patient versus control sera. Analysis of a validation cohort using qPCR of PEG-precipitated EV preparations revealed the over-representation of HSATI, HSATII, LINE1-P1, and Charlie 3 at the DNA but not RNA level, with receiver operating characteristic (ROC) area under the curve (AUC) ≥ 0.90. HSATI and HSATII DNAs co-purified with EVs prepared by precipitation and size exclusion chromatography but not by exosome immunocapture, indicative of packaging in a non-exosomal complex. The consistent over-representation of EV-associated repetitive element DNA sequences suggests their potential utility as biomarkers for OS and perhaps other cancers.
Highlights
Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults
To further evaluate if repetitive element DNAs that were more abundant in OS patient polyethylene glycol (PEG)-precipitations are associated with extracellular vesicle (EV), we examined whether they co-purified with EVs prepared by size exclusion chromatography (SEC) and exosome immunoaffinity capture
To identify new OS biomarkers, we investigated nucleic acid sequences associated with circulating EVs in OS patients
Summary
Osteosarcoma (OS) is the most common malignant bone tumor in children and young adults. This study aimed to identify circulating nucleic acid sequences associated with serum extracellular vesicle (EV) preparations at the time of OS diagnosis, as a step towards an OS early detection assay. Sequencing of small nucleic acids extracted from serum EV preparations revealed increased representation of diverse repetitive element sequences in OS patient versus control sera. The consistent over-representation of EV-associated repetitive element DNA sequences suggests their potential utility as biomarkers for OS and perhaps other cancers. Combined genetic predisposition and exposure to DNA damaging agents confers high risk; for example, relative risk for children with hereditary retinoblastoma increased from ~ 69 without such treatments to ~ 302 for radiotherapy and ~ 539 for radiotherapy plus chemotherapy in the largest treatment-stratified analysis[5]. No biomarkers have been shown to reliably detect naïve pre-symptomatic OS in predisposed individuals[13]
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