LAUSR

Background. Parathyroid tumors are characterized by genetic and epigenetic alterations resulting in aberrant expression of protein coding genes and non-coding RNAs. Although long non-coding RNAs (lncRNAs) play a regulatory role in endocrine cancer pathogenesis, a lncRNAs signature in human parathyroid tumors is still missing. Here we investigated the lncRNAs alterations, both at genomic and transcriptional level, in human non-familial parathyroid tumors. Methods. The expression of 90 lncRNAs was investigated in 4 parathyroid carcinomas (PCas), 12 adenomas (PAds) and 2 normal glands (PaNs) using a commercial array. Both unsupervised (hierarchical clustering-HCL and Principal Component Analysis-PCA) and supervised (Significance Analysis of Microarray, SAM) analyses were performed to identify differences in lncRNAs expression between the 3 tissue types. Significant lncRNAs were validated in a second set of parathyroid tissues including 7 PCas, 26 PAds, 6 atypical PAds (aPAds) and 4 PaNs. Genomic characterization of 21 PAds was performed by array Comparative Genomic Hybridization (aCGH). CDC73 and Multiple Endocrine Neoplasia 1 (MEN1) genes mutations were detected by Sanger sequencing. Results. HCL analysis of lncRNAs expression identified 2 major groups in which PaNs and PCas were distinguished. Nine lncRNAs were differentially expressed in parathyroid tissues. Specifically, KCNQ1OT1 and SNHG6 were enriched in PaNs, HAR1B, MEG3, HOXA3as and NEAT1 expression characterized PAds, whereas BC200, HOXA6as and WT1-AS were significantly upregulated in PCas. Besides confirming previous data, validation analysis highlighted a different lncRNAs expression pattern in PCas and aPAds according to CDC73 mutation status, with mutated tumors overexpressing the majority of the lncRNAs. Interestingly, BACE1-AS, KCNQ1OT1, NEAT1 and SNHG6 levels in PAds were significantly correlated with MEN1 levels while HAR1B upregulation was associated with chromosome 11 loss of heterozygosity (LOH). Conclusions. Overall these findings shed light on lncRNAs deregulation in parathyroid pathobiology. Parathyroid tumors histotypes are characterized by different lncRNAs signatures that are related to chromosome 11 derangements and to MEN1 inactivation. Finally, MEN1 may play an epigenetic role in lncRNAs regulation, supporting the important role of chromosome 11 in parathyroid tumorigenesis. Citation Format: Annamaria Morotti, Irene Forno, Valentina Andre, Vito Guarnieri, Andrea Terrasi, Rosa Maria Silipigni, Silvana Guerneri, Chiara Verdelli, Alfredo Scillitani, Leonardo Vicentini, Filomena Cetani, Edoardo Beretta, Sabrina Corbetta, Valentina Vaira. Insights into the non-coding genome of parathyroid tumors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3732.