ECE2018 Oral Communications Genomic and clinical aspects of endocrine tumours (5 abstracts)
LncRNAs profiling reveals epigenetic heterogeneity among human parathyroid tumor
Annamaria Morotti 1 , Chiara Verdelli 2 , Vito Guarnieri 3 , Filomena Cetani 4 , Rosa Silipigni 5 , Silvana Guerneri 5 , Alfredo Scillitani 6 , Leonardo Vicentini 7 , Edoardo Beretta 8 , Valentina Vaira 1 & Sabrina Corbetta 9
1Division of Pathology, Department of Pathophysiology and Transplantation, University of Milan, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy; 2Laboratory of Experimental Endocrinology, IRCCS Istituto Ortopedico Galeazzi, Milan, Italy; 3Genetic Medicine, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; 4Endocrine Unit 2, University Hospital of Pisa, Pisa, Italy; 5Medical Genetics Laboratory, Fondazione IRCCS Cà Granda, Ospedale Maggiore Policlinico, Milan, Italy; 6Endocrinology Unit, IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (FG), Italy; 7Endocrine Surgery, Istituto Auxologico Capitanio, Milan, Italy; 8Endocrine Surgery, IRCCS Ospedale San Raffaele, Milan, Italy; 9Endocrinology Service, Department of Biomedical Sciences for Health, IRCCS Istituto Ortopedico Galeazzi, University of Milan, Milan, Italy.
Long noncoding RNAs (LncRNAs) are transcripts of more than 200 nucleotides not translated into proteins. They carry out diverse functions, including transcriptional regulation in cis or trans, organization of nuclear domains, and regulation of proteins or RNA molecules. Aberrant expression of LncRNAs has been reported in human cancers; indeed, data in parathyroid tumors are lacking. Based on the profiling through lncProfilersTM qPCR Array with SYBR® green detection of 90 LncRNAs in a preliminary set of 4 parathyroid carcinomas (PCas), 12 parathyroid adenomas (PAds) compared wit 2 normal parathyroid glands (PaNs), SAM significance analysis identified 9 differentially expressed LncRNAs: 3 lncRNAs were upregulated in PCas (BC200, HOXA6-AS, WT1-AS), 4 lncRNAs were downregulated in PAds (HAR1B, HOXA3-AS, MEG3, NEAT1) and 2 downregulated in both PAds and PCas compared to PaNs (KCNQ1OT1, SNHG6). The 9 lncRNAs were validated in a second independent series of parathyroid samples including 7 PCas, 6 atypical PAds, 26 PAds and 4 PaNs. Unsupervised analysis of the LncRNAs expression levels in this set of 40 parathyroid samples, identified three clusters: cluster 1 was characterized by LncRNAs general donwnregulation, cluster 3 showed LncRNAs diffuse upregulation, while cluster 2 presented an intermediate pattern. Cluster 2 included all the 4 PaNs and a subset of PAds, while clusters 1 and 3 included PCas, atypical PAds and the remaining PAds. Patients affected with cluster 2 tumors had lower total and ionized calcium as well as PTH levels than patients with clusters 1 and 3 tumors. We characterized the genetic background of the parathyroid tumors by Array Comparative Genomic Hybridization (aCGH), direct sequencing of the MEN1 and CDC73 genes and MLPA for the MEN1 region. Array CGH identified monosomy of chromosome 11 in 9 (42%) PAds and loss of 1p in 7 (27%) PAds. MEN1 mutations were detected in 5 PAds, while CDC73 was mutated in 4 PCas. Interestingly, chromosome 11 monosomy and MEN1 mutations were more frequent in cluster 2 PAds; cluster 1 included most PAds with loss of 1p, while PCas had wild-type CDC73; CDC73-mutated PCas were grouped in cluster 3. Considering the MEN1 expression levels, we observed that PAds with downregulated MEN1 mRNA levels had low KCNQ1OT1, NEAT1 and SNHG6 expression levels, suggesting an epigenetic role for menin. Experiments aimed to investigate the effect of MEN1 silencing on the MEN1-associated LncRNAs are ongoing. In conclusion, parathyroid tumors show genetic and epigenetic heterogeneity affecting clinical presentation.
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Endocrine Abstracts
ISSN 1470-3947 (print) | ISSN 1479-6848 (online)
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