Uterine leiomyosarcoma and endometrial stromal sarcoma have unique miRNA signatures
Introduction
Uterine sarcomas are rare tumors, comprising 7% of all soft tissue sarcomas and about 3% of uterine malignancies [1], [2], [3]. Leiomyosarcoma (LMS) and endometrial stromal sarcoma (ESS) are the most common histological types [2], [3]. Adenosarcoma and carcinosarcoma are both mixed epithelial–mesenchymal tumors, but only the former have a true sarcomatous component, whereas carcinosarcomas are currently regarded as metaplastic carcinomas. ESS has been previously classified as low-grade or high-grade, later regarded as a single entity, and recently re-divided into low-grade and high-grade categories, although the latter group constitutes rare tumors [4].
MicroRNAs (miRNAs) are small (19–25 nucleotides), non-coding RNAs that post-transcriptionally regulate gene expression [5]. miRNAs are synthesized as a long double-stranded precursor called pri-miRNA by DNA polymerase II in the nucleus. Pri-miRNA is cleaved at specific sites by the RNAse Drosha inside the nucleus, producing a pre-miRNA which is exported to the cytoplasm by the exportin 5 protein, where it is processed by Dicer into mature miRNA. Mature miRNAs are subsequently activated through binding to the RNA-induced silencing complex (RISC) [6], [7]. Through the RISC, miRNAs can regulate their targets, mediating translational repression or degradation. The sequence at the 5′ end of the mature miRNA, called the “seed region”, binds its complementary sequence within the 3′ untranslated regions (UTR) of the target mRNA [8]. Perfect or near-perfect complementarity between the miRNA and its mRNA target results in mRNA degradation, whereas lesser complementarity leads to translational inhibition.
Data regarding the miRNA profile of uterine sarcomas is limited to date. An inverse association was reported for the miRNA Let-7 and its target high-mobility group AT-hook-2 (HMGA2) in uterine LMS [9]. miRNA profiles which differentiate uterine LMS from leiomyoma [10] or from different types of leiomyoma as well as smooth muscle tumors of uncertain malignant potential (STUMP) [11] have been described. In another report, the miRNA profiles of uterine sarcomas and carcinosarcomas were compared to those of patient-matched benign tissue [12].
Our group has previously reported on gene expression profiles which differentiate LMS from ESS [13] and primary LMS from metastatic LMS [14]. Similar data with respect to miRNA profiles are unavailable to date to the best of our knowledge. The present study compared the miRNA profiles of primary ESS, primary LMS and metastatic LMS.
Section snippets
Patients and material
Specimens consisted of 44 uterine sarcomas, including 9 primary uterine ESS, 17 primary uterine LMS and 18 metastatic LMS, submitted for routine diagnostic purposes to the Department of Pathology at the Norwegian Radium Hospital during the period 1993–2009. Tumors were snap-frozen and kept at − 70 °C. Frozen sections were evaluated for the presence of a > 80% tumor component and absence of necrosis. Diagnoses were established by an experienced gynecologic pathologist (BD) based on morphology and
Results
Forty-nine miRNAs were found to be differentially expressed between primary and. metastatic LMS, of which 4 were overexpressed and 45 underexpressed in the metastatic lesions. Comparative analysis of primary LMS and ESS identified 94 miRNAs that were significantly differentially expressed between these two sarcoma types, including 76 overexpressed in ESS and 18 overexpressed in LMS (p < 0.05; Supplementary Table 1 and Supplementary Figs. 1-A, -B).
Among the 20 miRNAs found to be most significantly
Discussion
ESS and LMS are both rare sarcomas affecting the uterine corpus. However, they differ considerably at the genotypic and phenotypic levels, as well as their clinical behavior. Our understanding of differences in the molecular drivers of each of these cancers is limited by the paucity of comparative molecular analyses of ESS and LMS. Beyond scientific interest, such studies may improve and expand the very limited panel available for differentiating these tumors in routine surgical pathology,
Financial acknowledgment
This work was supported by a grant from the National Sarcoma Foundation at the Norwegian Radium Hospital.
Conflict of interest statement
The authors declare that they have no competing interests.
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R.R. is affiliated with the David R. Bloom Center for Pharmacy and the Adolf and Klara Brettler Center for Research in Molecular Pharmacology and Therapeutics at The Hebrew University of Jerusalem, Israel.