title: Epigenetic regulation of SMARCB1 By miR-206, -381 and -671-5p is evident in a variety of SMARCB1 immunonegative soft tissue sarcomas, while miR-765 appears specific for epithelioid sarcoma. A miRNA study of 223 soft tissue sarcomas.
abstract: Complete/partial loss of SMARCB1 nuclear-immunopositivity is characteristic of a certain subset of soft tissue sarcomas (STSs). Our previous work showed that oncomiRs-206,-381, and 671-5p could silence the SMARCB1 mRNA and protein expression and that they display significant overexpression in epithelioid sarcomas (ESs). MiR-765 was overexpressed too, but functionally was inactive in the silencing. In the current work, using quantitative PCR, we conducted a miRNA study of 51 ESs, 20 rhabdoid tumors (RTs), 20 synovial sarcomas (SSs), 15 malignant peripheral nerve sheath tumors (MPNSTs), 11 myoepithelial carcinomas (MECs), and 10 extraskeletal myxoid chondrosarcomas (EMCSs) with complete/partial loss of SMARCB1 nuclear immunostain, in contrast to controls (SMARCB1-immunopositive) of 96 STSs, 13 melanomas and 10 sarcomatoid carcinomas. The SMARCB1 genetic status of ESs was determined by MLPA and FISH. A subset of ESs (5/51) showed biallelic deletion of SMARCB1 with no overexpression of any miRNA, suggesting these tumors could be the counterpart of pediatric RT, at least genetically. Another subset (5/51) was genetically either intact or monoallelic deleted with at least threefold overexpression of one of miR-206,-381,-671-5p, suggesting epigenetic regulation only. 39/51 ESs had a biallelic deletion (>20% by FISH and/or by MLPA) but with overexpressed miR-206,-381, and 671-5p, suggesting intratumoral heterogeneity, i.e., both genetic and epigenetic regulation. At least threefold overexpression of one of miR-206,-381, and 671-5p was detected in all MPNSTs, EMCSs, SSs and 7 MCs. Except for ESs, four SSs and one MPNST, there was no event above threefold overexpression of miR-765 among all 195 tested tumors. Our results suggest a general role of miR-206,-381, and 671-5p in SMARCB1 gene silencing of ES, MC, EMCS, MPNST and SS. In the future, miR-765 could possibly be a diagnostic tool for ES because of its 97% specificity and 80% sensitivity. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Zoltán
authors.initials: Z
authors.lastname: Sápi
authors.affiliation: Department of Pathology and Experimental Cancer Research, Semmelweis University, Budapest, Hungary.
authors.forename: Gergő
authors.initials: G
authors.lastname: Papp
authors.affiliation: Department of Orthopedics, Semmelweis University, Budapest, Hungary.
authors.forename: Miklós
authors.initials: M
authors.lastname: Szendrői
authors.affiliation: Oncology Department, Military Hospital, Budapest, Hungary.
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Pápai
authors.affiliation: Surgical and Molecular Tumor Pathology Centre, National Institute of Oncology, Budapest, Hungary.
authors.forename: Vanda
authors.initials: V
authors.lastname: Plótár
authors.affiliation: Department of Pathology, University of Chicago Medicine, Chicago, IL.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krausz
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA.
authors.forename: Christopher D M
authors.initials: CD
authors.lastname: Fletcher
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002648:Child; D002675:Child, Preschool; D002813:Chondrosarcoma / Q000235:genetics / Q000473:pathology; D044127:Epigenesis, Genetic; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D020868:Gene Silencing; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D007223:Infant; D008297:Male; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D009208:Myoepithelioma / Q000235:genetics / Q000473:pathology; D018204:Neoplasms, Connective and Soft Tissue / Q000235:genetics / Q000473:pathology; D009442:Neurilemmoma / Q000235:genetics / Q000473:pathology; D018335:Rhabdoid Tumor / Q000235:genetics / Q000473:pathology; D000071796:SMARCB1 Protein / Q000096:biosynthesis / Q000235:genetics*; D012509:Sarcoma / Q000145:classification / Q000235:genetics* / Q000473:pathology; D013584:Sarcoma, Synovial / Q000235:genetics / Q000473:pathology; D055815:Young Adult
chemical_list: C546087:MIRN206 microRNA, human; C588249:MIRN381 microRNA, human; C568637:MIRN671 microRNA, human; C000600151:MIRN765 microRNA, human; D035683:MicroRNAs; D000071796:SMARCB1 Protein; C513266:SMARCB1 protein, human