Oncogenic Dysregulation of Circulating Noncoding RNAs: Novel Challenges and Opportunities in Sarcoma Diagnosis and Treatment

SIMPLE SUMMARY: Body fluids contain different classes of RNA molecules such as protein-coding messenger RNAs (mRNA) and noncoding RNAs, including microRNAs (miRNAs), long noncoding RNAs (lncRNAs) and circular RNAs (circRNAs). These circulating RNAs can travel naked or packed into extracellular vesicles and display valuable potential as non-invasive biomarkers of sarcoma malignancy. In this review, we summarize current knowledge on the possible functions of these circulating RNAs and discuss their possible exploitation as novel markers to improve sarcoma diagnosis and prognosis. Despite the recent advance in technological tools have improved protocols for the extraction and detection of circulating RNA, many aspects related to the biology of these molecules remain to be elucidated. In particular, the lack of standardization in the assessment of these markers makes difficult their adoption into clinical practice. ABSTRACT: Sarcomas comprise a heterogeneous group of rare mesenchymal malignancies. Sarcomas can be grouped into two categories characterized by different prognosis and treatment approaches: soft tissue sarcoma and primary bone sarcoma. In the last years, research on novel diagnostic, prognostic or predictive biomarkers in sarcoma management has been focused on circulating tumor-derived molecules as valuable tools. Liquid biopsies that measure various tumor components, including circulating cell-free DNA and RNA, circulating tumor cells, tumor extracellular vesicles and exosomes, are gaining attention as methods for molecular screening and early diagnosis. Compared with traditional tissue biopsies, liquid biopsies are minimally invasive and blood samples can be collected serially over time to monitor cancer progression. This review will focus on circulating noncoding RNA molecules from liquid biopsies that are dysregulated in sarcoma malignancies and discuss advantages and current limitations of their employment as biomarkers in the management of sarcomas. It will also explore their utility in the evaluation of the clinical response to treatments and of disease relapse. Moreover, it will explore state-of-the-art techniques that allow for the early detection of these circulating biomarkers. Despite the huge potential, current reports highlight poor sensitivity, specificity, and survival benefit of these methods, that are therefore still insufficient for routine screening purposes.