Heterogeneous Transcriptional Landscapes in Human Sporadic Parathyroid Gland Tumors

The expression of several key molecules is altered in parathyroid tumors due to gene mutations, the loss of heterozygosity, and aberrant gene promoter methylation. A set of genes involved in parathyroid tumorigenesis has been investigated in sporadic parathyroid adenomas (PAds). Thirty-two fresh PAd tissue samples surgically removed from patients with primary hyperparathyroidism (PHPT) were collected and profiled for gene, microRNA, and lncRNA expression (n = 27). Based on a gene set including <i>MEN1</i>, <i>CDC73</i>, <i>GCM2</i>, <i>CASR</i>, <i>VDR</i>, <i>CCND1</i>, and <i>CDKN1B</i>, the transcriptomic profiles were analyzed using a cluster analysis. The expression levels of <i>CDC73</i> and <i>CDKN1B</i> were the main drivers for clusterization. The samples were separated into two main clusters, C1 and C2, with the latter including two subgroups of five PAds (C2A) and nineteen PAds (C2B), both differing from C1 in terms of their lower expression of <i>CDC73</i> and <i>CDKN1B</i>. The C2A PAd profile was also associated with the loss of TP73, an increased expression of <i>HAR1B</i>, <i>HOXA-AS2</i>, and <i>HOXA-AS3</i> lncRNAs, and a trend towards more severe PHPT compared to C1 and C2B PAds. C2B PAds were characterized by a general downregulated gene expression. Moreover, <i>CCND1</i> levels were also reduced as well as the expression of the lncRNAs <i>NEAT1</i> and <i>VLDLR-AS1</i>. Of note, the deregulated lncRNAs are predicted to interact with the histones H3K4 and H3K27. Patients harboring C2B PAds had lower ionized and total serum calcium levels, lower PTH levels, and smaller tumor sizes than patients harboring C2A PAds. In conclusion, PAds display heterogeneous transcriptomic profiles which may contribute to the modulation of clinical and biochemical features. The general downregulated gene expression, characterizing a subgroup of PAds, suggests the tumor cells behave as quiescent resting cells, while the severity of PHPT may be associated with the loss of p73 and the lncRNA-mediated deregulation of histones.