Abstract
Osteosarcoma is the most common malignant bone tumor in children and young adults. Despite the use of surgery and multi-agent chemotherapy, osteosarcoma patients who have a poor response to chemotherapy or develop relapses have a dismal outcome. Identification of biomarkers for active disease may help to monitor tumor burden, detect early relapses, and predict prognosis in these patients. In this study, we examined whether circulating miRNAs can be used as biomarkers in osteosarcoma patients. We performed genome-wide miRNA profiling on a discovery cohort of osteosarcoma and control plasma samples. A total of 56 miRNAs were upregulated and 164 miRNAs were downregulated in osteosarcoma samples when compared to control plasma samples. miR-21, miR-221 and miR-106a were selected for further validation based on their known biological importance. We showed that all three circulating miRNAs were expressed significantly higher in osteosarcoma samples than normal samples in an independent cohort obtained from the Children’s Oncology Group. Furthermore, we demonstrated that miR-21 was expressed significantly higher in osteosarcoma tumors compared with normal bone controls. More importantly, lower expressions of miR-21 and miR-221, but not miR-106a, significantly correlated with a poor outcome. In conclusion, our results indicate that miR-21, miR-221 and miR-106a were elevated in the circulation of osteosarcoma patients, whereas tumor expressions of miR-21 and miR-221 are prognostically significant. Further investigation of these miRNAs may lead to a better prognostic method and potential miRNA therapeutics for osteosarcoma.
Highlights
Osteosarcoma (OS) is the most frequent primary malignant bone tumor in pediatric patients comprising of 55% of all bone tumors [1, 2]
Our results show that three miRNAs are significantly overexpressed in OS plasma compared to control samples and could be used as non-invasive biomarkers for OS. miR-21 was significantly overexpressed in OS tumor samples, and tumor expression of miR-21 and miR-221 correlated with prognosis
To identify circulating biomarkers that were associated with OS, we analyzed the abundance levels of 752 miRNAs in a discovery set of OS plasma samples (n = 32) versus normal plasma samples from healthy www.impactjournals.com/oncotarget donors and children with noncancerous diseases (n = 8) using a locked nucleic acid (LNA)-based quantitative reverse transcription-polymerase chain reaction platform
Summary
Osteosarcoma (OS) is the most frequent primary malignant bone tumor in pediatric patients comprising of 55% of all bone tumors [1, 2]. Introduction of combination chemotherapy in the 1970s and surgery for localized tumor led to a significant increase in survival rates to 60–70%. Several clinical features are known to be strong prognostic predictors, such as primary metastases, tumor size, complete surgical resection and histologic response to chemotherapy [5]. A retrospective study demonstrated that the time of identification of pulmonary metastases, which is the most prevalent form of metastases in OS, has a significant effect on survival rates. Biomarkers can improve or complement the accuracy, sensitivity and specificity of the routinely used detection and imaging methods. No sensitive and specific non-invasive, diagnostic biomarker to distinguish OS from healthy controls exists.
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