The microRNA cluster C19MC is deregulated in parathyroid tumours

A subset of over-expressed microRNAs identified in parathyroid carcinomas (Ca) compared to normal glands, belong to C19MC, a cluster on chromosome 19q13.4 involved in stem cell biology and tumorigenesis. In the present study, the expression of C19MC-MIR371-3 clusters and the molecular mechanisms presiding their modulation were investigated in a series of 6 normal parathyroids, 24 adenomas (Ad), 15 Ca and 5 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 significantly difference in expression between Ca and Ad (P=0.0003) and it positively correlated with serum calcium, PTH and tumour weight. In regard to the molecular mechanism determining C19MC cluster activation, we could detect C19MC copy-number gain in 10 Ca (67%) extending distal to the MIR371-3 cluster in almost all samples. Conversely, only 4 Ad (16%) showed C19MC amplification, with one case presenting distal genomic aberration to MIR371-3. Globally, copy number 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 microRNAs expression levels, loss of C19MC promoter methylation was significantly associated to Ca and metastatic disease (P=0.01). In conclusion, C19MC cluster aberrations are a characteristic of Ca respect to Ad. Altogether, these evidences point toward a role for 19q13.4 microRNAs clusters as oncogenes in parathyroid tumorigenesis.