miRNAs are ∼22nt long non-coding small RNAs that negatively regulate gene expression at the post-transcriptional level and play key roles in fundamental cellular processes. Deregulation of miRNAs has been observed in several diseases including cancer. Sarcomas are a heterogeneous group of rare mesenchymal malignancies with high rates of metastasis and local recurrence. A large variety of histotypes with very few reliable markers makes sarcoma diagnosis challenging. Hence, a refined classification scheme with novel diagnostic, prognostic and predictive markers would be clinically valuable. Additionally, tumor specific alterations in the miRNA expression profile may lead to the identification of miRNA targets important in sarcoma tumor biology.

The diagnostic value of miRNA expression profiling was assessed in a mixed series of 161 sarcomas representing 12 histopathological subtypes, 5 normal smooth muscle, 4 normal skeletal muscle and 4 normal adipose tissues, using Agilent miRNA oligoarrays containing 470 human and 64 viral miRNAs. High-throughput miRNA sequencing (Illumina) was performed in a subset (n=10) of these tumors to validate results from the array-based expression profiling.

An unsupervised cluster analysis performed on the 174 tumor and normal samples revealed groups based predominantly on diagnosis and tissue-type. All hemangiopericytomas and dermatofibrosarcomas, most rhabdomyosarcomas, Ewing's sarcomas, myxoid/round-cell liposarcomas, synovial sarcomas, leiomyosarcomas, osteosarcomas, normal smooth muscle, normal skeletal muscle and normal adipose tissue formed distinct clusters. About half of the pleomorphic/dedifferentiated/well-differentiated liposarcomas and fibrosarcomas and a quarter of the malignant peripheral nerve sheath tumors grouped together whereas most of the malignant fibrous histiocytomas clustered poorly. Discriminatory miRNAs were identified for the various subtypes (e.g., miR-146, miR-99 and miR-222 were highly expressed in the hemangiopericytomas, miR-375, miR-206 and miR-1 in the rhabdomyosarcomas, miR-181, miR-101 and miR-10 in the Ewing's sarcomas, miR-140-3p, miR-199 and miR-152 in osteosarcomas and miR-143, miR-145 and miR-28 in leiomyosarcomas). miRNAs that distinguished normal skeletal muscle from rhabdomysarcomas (e.g. miR-130, miR-133), normal smooth muscle from leiomyosarcomas (e.g. miR-142, miR-376) and normal adipose tissue from liposarcomas (e.g. miR-155, miR-365) were also identified. The results from sequencing were highly correlated with the results from the microarray analysis.

Distinct miRNA expression profiles that correlate with lineage and tumor biology were identified not only in sarcomas with simple type-specific genetic alterations but also in the pleomorphic subtypes suggesting an important role for miRNAs in their tumorigenesis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 3024.