C19MC Amplification Research Articles

The microRNA cluster C19MC is deregulated in parathyroid tumours

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.

Abstract 4355: The C19MC miRNA polycistron are frequent targets of gene amplification in aggressive primitive neuroectodermal brain tumors and encode oncogenic miRNAs that inhibit normal neural stem cell differentiation

Abstract Embryonal brain tumors which include medulloblastoma and primitive neuroectodermal brain tumors (CNS-PNET) comprise the largest group of malignant pediatric brain tumors and account for substantial cancer related morbidity and mortality in childhood. Unlike medulloblastoma, a common, cerebellar PNET, few CNS-PNET arising in extracerebellar locations have been characterized. Lack of insight into the molecular pathogenesis of CNS-PNET is a major obstacle towards development of much-needed disease-specific models and treatments for these devastating tumors. In this study, we performed high-resolution DNA copy number analysis on a substantial collection of primary CNS-PNET obtained through an international collaborative group, and discovered a frequent amplicon in 25% (11/46) of CNS-PNET which span 34 protein coding genes and two miRNA clusters, C19MC and miR-371-373, on chr19q13.41. Detailed mapping studies revealed C19MC, which encode 54 primate-specific miRNAs, as the specific target of gene amplification resulting in striking tumor-specific overexpression of a sub-set of miRNAs, including miR-520 g and miR- 517c. Stable expression of miR-520 g and miR-517c promoted in vitro and in vivo oncogenicity and conferred cell survival in tumor cell lines. Strikingly expression of both miR-520g and 517c promoted growth and inhibited differentiation of untransformed normal human neural stem cells. Notably, clinicopathologic analyses revealed that C19MC amplification identifies a distinct group of CNS-PNET with similar gene expression profiles, characteristic histology, and much poorer survival. Our aggregate findings which point to C19MC as an important, new oncogenic locus in a human cancer, have significant implications for the diagnosis and clinical management of embryonal brain tumors in children. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4355.