Promoter hypermethylation inactivates CDKN2A, CDKN2B and RASSF1A genes in sporadic parathyroid adenomas

Abstract

Cyclin D1, a G1-S phase regulator, is upregulated in parathyroid adenomas. Since cyclin-dependent kinase (CDK) inhibitors, CDKN2A and CDKN2B, and RASSF1A (Ras-association domain family 1, isoform A) are involved in G1-S phase arrest and act as potential tumor suppressor genes, we aimed to study potential methylation-mediated inactivation of these genes in parathyroid adenomas. Gene expressions of cyclin D1 (CCND1) and regulatory molecules (CDKN2A, CDKN2B and RASSF1A) was analysed in parathyroid adenoma tissues (n = 30). DNA promoter methylation of cyclin D1 regulators were assessed and correlated with clinicopathological features of the patients. Gene expression analysis showed a relative fold reductions of 0.35 for CDKN2A (p = 0.01), 0.45 for CDKN2B (P = 0.02), and 0.39 for RASSF1A (p < 0.01) in adenomatous compared to normal parathyroid tissue. There was an inverse relationship between the expressions of CDKN2A and CDKN2B with CCND1. In addition, the promoter regions of CDKN2A, CDKN2B, and of RASSF1A were significantly hyper-methylated in 50% (n = 15), 47% (n = 14), and 90% (n = 27) of adenomas respectively. In contrast, no such aberrant methylation of these genes was observed in normal parathyroid tissue. So, promoter hypermethylation is associated with down-regulation of CCND1 regulatory genes in sporadic parathyroid adenomas. This dysregulated cell cycle mechanism may contribute to parathyroid tumorigenesis.

Identification by TCGA database search of five genes that are aberrantly expressed and involved in hepatocellular carcinoma potentially via DNA methylation changes

“…P16 is well-recognized as a tumor suppressor gene which is silenced by hyper-methylation of CpGi in human cancers and restores expression by DNA methyltransferase inhibitors [ 10 , 14 , 25 , 26 ]. We investigated the DNA methylation and gene expression of P16 using the TCGA database.…”

A Role for Circular Non-Coding RNAs in the Pathogenesis of Sporadic Parathyroid Adenomas and the Impact of Gender-Specific Epigenetic Regulation

“…The predicted genes associated with the differentially expressed circ-RNAs are depicted in Table 2. Two circRNAs, hsa_circRNA_404337 and hsa_circRNA_051799, interact with genes that have been shown to associate with molecular pathways that are involved in the pathogenesis of sporadic PAs, such as CDKN1B and CDK1, respectively [17,18].…”

Molecular genetic insights into sporadic primary hyperparathyroidism

“…The paucity of genetic lesions in CDKI genes suggests they are not common drivers of sporadic parathyroid tumorigenesis; however, they may act as rare predisposition alleles, and other evidence suggests they may also be downstream targets of different drivers. Aberrant methylation and low mRNA and/or protein expression of CDKN1A, encoding P21CIP1 (p21); CDKN1B (p27); CDKN2A, encoding P16INK4A (p16); CDKN2B, encoding P15INK4B (p15); and CDKN2C (p18) have been reported; a drastic reduction to no detectable mRNA expression of CDKN1A in 53% and of CDKN2C in 42% of one cohort further suggest that CDKI inactivation is functionally associated with parathyroid adenoma (Buchwald et al 2004, Starker et al 2011, Sulaiman et al 2013, Arya et al 2017, Borsari et al 2017.…”

“…APC promoter 1A was found to be hypermethylated in 56-71% of typical parathyroid adenomas (Juhlin et al 2010, Sulaiman et al 2013. RASSF1A and three members of the family of secreted frizzledrelated proteins (SFRPs), all of which are antagonistic to Endocrine-Related Cancer the Wnt/β-catenin signaling pathway, were also found to be hypermethylated and their expression downregulated in a similar fashion (Juhlin et al 2010, Starker et al 2011, Sulaiman et al 2013, Arya et al 2017. Additional genetic and epigenetic evidence will be required to demonstrate a causative role (or a crucial downstream role) for APC, RASSF1A, SFRPs, and/or their transcriptional regulators in parathyroid tumors.…”