title: The two stem cell microRNA gene clusters C19MC and miR-371-3 are activated by specific chromosomal rearrangements in a subgroup of thyroid adenomas.
abstract: Thyroid adenomas are common benign human tumors with a high prevalence of about 5% of the adult population even in iodine sufficient areas. Rearrangements of chromosomal band 19q13.4 represent a frequent clonal cytogenetic deviation in these tumors making them the most frequent non-random chromosomal translocations in human epithelial tumors at all. Two microRNA (miRNA) gene clusters i.e. C19MC and miR-371-3 are located in close proximity to the breakpoint region of these chromosomal rearrangements and have been checked for a possible up-regulation due to the genomic alteration. In 4/5 cell lines established from thyroid adenomas with 19q13.4 rearrangements and 5/5 primary adenomas with that type of rearrangement both the C19MC and miR-371-3 cluster were found to be significantly overexpressed compared to controls lacking that particular chromosome abnormality. In the remaining cell line qRT-PCR revealed overexpression of members of the miR-371-3 cluster only which might be due to a deletion accompanying the chromosomal rearrangement in that case. In depth molecular characterization of the breakpoint in a cell line from one adenoma of this type reveals the existence of large Pol-II mRNA fragments as the most likely source of up-regulation of the C19MC cluster. The up-regulation of the clusters is likely to be causally associated with the pathogenesis of the corresponding tumors. Of note, the expression of miRNAs miR-520c and miR-373 is known to characterize stem cells and in terms of molecular oncology has been implicated in invasive growth of epithelial cells in vitro and in vivo thus allowing to delineate a distinct molecular subtype of thyroid adenomas. Besides thyroid adenomas rearrangements of 19q13.4 are frequently found in other human neoplasias as well, suggesting that activation of both clusters might be a more general phenomenon in human neoplasias.
authors.affiliation: Center for Human Genetics, University of Bremen, Bremen, Germany.
authors.forename: Volkhard
authors.initials: V
authors.lastname: Rippe
authors.forename: Lea
authors.initials: L
authors.lastname: Dittberner
authors.forename: Verena N
authors.initials: VN
authors.lastname: Lorenz
authors.forename: Norbert
authors.initials: N
authors.lastname: Drieschner
authors.forename: Rolf
authors.initials: R
authors.lastname: Nimzyk
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Sendt
authors.forename: Klaus
authors.initials: K
authors.lastname: Junker
authors.forename: Gazanfer
authors.initials: G
authors.lastname: Belge
authors.forename: Jörn
authors.initials: J
authors.lastname: Bullerdiek
mesh_terms: D000236:Adenoma / Q000235:genetics*; D045744:Cell Line, Tumor; D002875:Chromosomes / Q000648:ultrastructure*; D002888:Chromosomes, Human, Pair 19; D015972:Gene Expression Regulation, Neoplastic; D015321:Gene Rearrangement; D006801:Humans; D017404:In Situ Hybridization, Fluorescence / Q000379:methods; D035683:MicroRNAs / Q000235:genetics*; D008969:Molecular Sequence Data; D005810:Multigene Family; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013234:Stem Cells / Q000166:cytology*; D013964:Thyroid Neoplasms / Q000235:genetics*
chemical_list: C554834:MIRN371 microRNA, human; D035683:MicroRNAs; D015514:Oncogene Proteins, Fusion