Signatures of circulating microRNA in four sarcoma subtypes

Abstract

Background: Sarcomas are rare malignant tumors of mesenchymal origin. The discovery of circulating biomarkers with high diagnostic value could supplement diagnosis of this heterogenous group of tumors. The aim of this study was to identify the profiles of circulating miRNA (c-miRNAs) in four groups of common bone and soft tissue sarcomas. Methods: At the time of diagnosis, blood samples were collected from 86 patients: 36 with locally advanced/unresectable/metastatic gastrointestinal stromal tumor (GIST) who received first-line treatment with imatinib; 16 with locally advanced osteosarcoma (OS); 26 with locally advanced synovial sarcoma (SS); and eight with locally advanced Ewing sarcoma (ES). In addition, samples were collected from 30 healthy controls. C-miRNAs were isolated using a miRCURY RNA Isolation Kit, followed by preparation of cDNA libraries and sequencing on the Ion Proton platform. Results: Pair-wise comparisons identified 156 unique c-miRNAs (adjusted P-value < 0.05) showing significant dysregulation between controls and patients; of these, 24, 36, 42, and 99 differentiated controls from pretherapeutic OS, SS, ES, and GIST, respectively. Ten c-miRNAs were commonly altered in at least three sarcoma types. Receiver operating characteristic curves and area under the curve (ROC-AUC) analyses revealed that a four-miRNA diagnostic classifier was able to differentiate controls from ES, GIST, OS, and SS, with AUC-ROC values of 1, 0.97, 0.95, and 0.94, respectively. Conclusions: Aberrant miRNA expression signatures were identified in serum from patients with four different sarcoma subtypes. Differences in miRNA expression profiles between sarcoma patients and healthy volunteers suggest that miRNAs may play a role in sarcoma development.

The new horizon of liquid biopsy in sarcoma: the potential utility of circulating tumor nucleic acids

“…Correspondingly, epigenetics variations in sarcomas mainly encompass three types: DNA methylation, histone modification and non-coding RNA modifications [52,53]. To date, only circulating non-coding RNAs , mainly microRNAs, have been studied in sarcoma liquid biopsy samples [38,40,54,55]. Previous studies have demonstrated that the levels of ctNAs in sarcomas are associated with tumorigenesis, progression and resistance to therapy [40,46,50,54,[56][57][58][59][60].…”

“…Increasing evidence indicates that the miRNA expression profile can be used to distinguish many tumor types, including sarcomas [54,167]. miR-1 and miR-113a/b which are regulators of myogenesis, were significantly overexpressed in LMS [58,168].…”

“…Gastrointestinal stromal tumor (GIST) is the most common gastrointestinal sarcoma with an incidence of 15-20 cases per million per year [54,171].…”

Non-Coding RNAs, a Novel Paradigm for the Management of Gastrointestinal Stromal Tumors

“…It is evident that non-coding RNAs can be exploited as diagnostic, prognostic and predictive biomarkers. The investigations carried out with GIST report diagnostic miRNA classifiers that distinguish GIST from other sarcomas [80,88,134], identify histological and molecular subtypes [85,98] and define location-specific markers [85]. Of particular clinical interest are the miRNAs associated with relapse risk [84,94,95,98,101,[108][109][110][111][112]135] that may be used to predict tumor recurrence and metastasis.…”

“…Only few investigators examined the miRNA profiles in serum samples. Distinct serum miRNA expression patterns were observed between GIST patients and healthy controls [134] and miR-518e-5p was identified a classifier for imatinib resistance [119]. Circulating miRNAs or other non-coding RNAs-either packaged in extracellular vesicles or not-may signal tumor recurrence, development of drug resistance and tumor progression or indicate metastasis.…”