Endocrine Abstracts

The expression of key molecules involved in fundamental cell processes and epigenetic gene expression modulation is altered in human parathyroid tumours, due to gene mutations, loss of heterozygosity, aberrant gene promoter methylation, DNA copy number variations. We performed a gene profiling of 26 parathyroid tumorigenesis-related genes in a series of 32 sporadic parathyroid adenomas (PAds) surgically removed from patients with primary hyperparathyroidism, with the aim to detect specific gene signatures. Gene expression data were analyzed by unsupervised hierarchical clustering analysis using Euclidean wardd2. Clusterization was performed considering the expression of oncosuppressors (MEN1, CDC73, RASSF1A, YAP1, CTNNB1), embryonic transcription factors (GCM2, TBX1, PAX1, GATA3), cell cycle genes (CCND1, CDKN1B/p27, CDKN1A/p21, TP73), and long noncoding RNAs (NEAT1, HAR1B, HOXA3AS, HOXA6AS, VLDLR-AS1, SNHG6). Additionally, all PAd samples were profiled for parathyroid-related genes (CASR, VDR, PTH) and microRNAs (miR-372, miR-517c, miR-126-5p, miR-93-5p). Three distinct transcriptional signatures were identified: cluster 1 (C1) included 9 PAds, while clusters 2A (C2A) and 2B (C2B) included 18 and 5 PAds, respectively. Principal components analysis showed that the main driver was represented by the expression of the LncRNA HAR1B (PC1, 88.4% of variance), followed by TP73 (PC2, 3.8%) and CDKN1B/p27 (PC3, 3.5%). PAds included in C2A had lower expression levels of the oncosuppressors CDC73, RASSF1A, CTNNB1, and of the transcription factors GCM2, GATA3, TBX1, PAX1 than C1 PAds. Interestingly, PAds in C2A had lower levels of CCND1 than C1 and C2B, and concomitantly lower levels of the proapoptotic RASSF1A-induced gene TP73. Moreover, HAR1B, HOXA3AS, VLDRAS1, SNHG6 expression levels were lower in C2A PAds. Besides, C2A and C2B included 4 PAds overexpressing the C19MC genes miR-372 and miR-517c. However, the gene expression signature of PAds included in C2A differed from that of C2B PAds, which had higher expression of MEN1 and YAP1, and of HOXA6AS. Interestingly, the gene signatures of PAds in C2A and C2B were associated with deeply reduced expression of CASR and VDR when compared with PAds in C1. Biochemical parameters, namely circulating ionized calcium ([Ca²⁺]), total calcium and PTH were similar in patients harbouring PAds included in C2A and C1, while the gene signature of PAds in C2B was associated with higher Ca²⁺ and total calcium. No difference in age at diagnosis as well as tumour size could be detected. In conclusion, in PAds transcriptional signature of critical genes involved in parathyroid tumorigenesis was heterogeneous, suggesting the role of several pathways, which claimed to be investigated.