title: The microRNA cluster C19MC is deregulated in parathyroid tumours.
abstract: A subset of over-expressed microRNAs (miRNAs) identified in parathyroid carcinomas (Ca) compared to normal glands belongs to C19MC, a cluster on chromosome 19q13.4 involved in stem cell biology and tumourigenesis. In this study, the expression of C19MC-MIR371-3 clusters and the molecular mechanisms presiding their modulation were investigated in a series of six normal parathyroids, 24 adenomas (Ad), 15 Ca and five matched metastases. The general expression levels of C19MC or MIR371-3 clusters in Ad lesions did not differ from normal glands, while they distinguished Ad from Ca at unsupervised hierarchical cluster analysis (P=0.0008). MIR517C showed the most significant difference in expression between Ca and Ad (P=0.0003) and it positively correlated with serum calcium, parathormone and tumour weight. In regard to the molecular mechanism determining C19MC cluster activation, we could detect C19MC copy number (CN) gain in ten Ca (67%) extending distal to the MIR371-3 cluster in almost all samples. Conversely, only four Ad (16%) showed C19MC amplification, with one case presenting distal genomic aberration to MIR371-3. Globally, CN variations of 19q13.4 loci were significantly associated with MIR517C up-regulation (P=0.006). Opposite to normal glands where C19MC promoter was methylated, hypomethylation occurred in 15 out of 30 analysed tumours. Though the epigenetic status did not correlate with C19MC miRNA expression levels, loss of C19MC promoter methylation was significantly associated with Ca and metastatic disease (P=0.01). In conclusion, C19MC cluster aberrations are a characteristic of Ca with respect to Ad. Altogether, these evidences point towards a role for 19q13.4 miRNA clusters as oncogenes in parathyroid tumourigenesis.
authors: Division of Pathology, Fondazione IRCCS Cà Granda Ospedale Maggiore Policlinico, Milan, Italy.
authors: Valentina
authors: V
authors: Vaira
authors: Francesca
authors: F
authors: Elli
authors: Irene
authors: I
authors: Forno
authors: Vito
authors: V
authors: Guarnieri
authors: Chiara
authors: C
authors: Verdelli
authors: Stefano
authors: S
authors: Ferrero
authors: Alfredo
authors: A
authors: Scillitani
authors: Leonardo
authors: L
authors: Vicentini
authors: Filomena
authors: F
authors: Cetani
authors: Giovanna
authors: G
authors: Mantovani
authors: Anna
authors: A
authors: Spada
authors: Silvano
authors: S
authors: Bosari
authors: Sabrina
authors: S
authors: Corbetta
mesh_terms: D000236:Adenoma / Q000235:genetics* / Q000473:pathology; D000368:Aged; D002888:Chromosomes, Human, Pair 19; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D008745:Methylation; D035683:MicroRNAs / Q000235:genetics; D008875:Middle Aged; D005810:Multigene Family; D010282:Parathyroid Neoplasms / Q000235:genetics* / Q000473:pathology; D011401:Promoter Regions, Genetic; D012016:Reference Values
chemical_list: C554834:MIRN371 microRNA, human; C546349:MIRN517 microRNA, human; D035683:MicroRNAs