title: The miR-17-92 cluster and its target THBS1 are differentially expressed in angiosarcomas dependent on MYC amplification.
abstract: Angiosarcomas (ASs) represent a heterogeneous group of malignant vascular tumors that may occur spontaneously as primary tumors or secondarily after radiation therapy or in the context of chronic lymphedema. Most secondary ASs have been associated with MYC oncogene amplification, whereas the role of MYC abnormalities in primary AS is not well defined. Twenty-two primary and secondary ASs were analyzed by array-comparative genomic hybridization (aCGH) and by deep sequencing of small RNA libraries. By aCGH and subsequently confirmed by fluorescence in situ hybridization, MYC amplification was identified in three out of six primary tumors and in 8 out of 12 secondary AS. We have also found MAML1 as a new potential oncogene in MYC-amplified AS. Significant upregulation of the miR-17-92 cluster was observed in MYC-amplified AS compared to AS lacking MYC amplification and the control group (other vascular tumors, nonvascular sarcomas). Moreover, MYC-amplified ASs were associated with a significantly lower expression of thrombospondin-1 (THBS1) than AS without MYC amplification or controls. Altogether, our study implicates MYC amplification not only in the pathogenesis of secondary AS but also in a subset of primary AS. Thus, MYC amplification may play a crucial role in the angiogenic phenotype of AS through upregulation of the miR-17-92 cluster, which subsequently downregulates THBS1, a potent endogenous inhibitor of angiogenesis.
authors.affiliation: Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. italiano@bergonie.org
authors.forename: Antoine
authors.initials: A
authors.lastname: Italiano
authors.forename: Rachael
authors.initials: R
authors.lastname: Thomas
authors.forename: Matthew
authors.initials: M
authors.lastname: Breen
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Aimee M
authors.initials: AM
authors.lastname: Crago
authors.forename: Samuel
authors.initials: S
authors.lastname: Singer
authors.forename: Raya
authors.initials: R
authors.lastname: Khanin
authors.forename: Robert G
authors.initials: RG
authors.lastname: Maki
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Mihailovic
authors.forename: Markus
authors.initials: M
authors.lastname: Hafner
authors.forename: Tom
authors.initials: T
authors.lastname: Tuschl
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D055028:Comparative Genomic Hybridization; D004268:DNA-Binding Proteins / Q000096:biosynthesis / Q000235:genetics; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D016259:Genes, myc; D006394:Hemangiosarcoma / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D017404:In Situ Hybridization, Fluorescence; D008297:Male; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics*; D008875:Middle Aged; D016271:Proto-Oncogene Proteins c-myc / Q000096:biosynthesis / Q000235:genetics; D062085:RNA, Long Noncoding; D017423:Sequence Analysis, RNA; D019700:Thrombospondin 1 / Q000096:biosynthesis / Q000235:genetics*; D014157:Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D019043:Vascular Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism
chemical_list: D004268:DNA-Binding Proteins; C430872:MAML1 protein, human; C568997:MIR17HG, human; D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D062085:RNA, Long Noncoding; D019700:Thrombospondin 1; D014157:Transcription Factors