This suggests that additional constitutional genetic mutations may contribute to the variation in malignant potential and clinical behavior of parathyroid tumors in MEN1.
These identified miRNAs could be revealed as prognostic and diagnostic biomarkers for parathyroid tumors to improve the diagnosis of MEN1 neoplasia and other syndromes.
Using a novel genome-wide methylation analysis, we studied tissues from MEN1-parathyroid tumors, Men1 knockout (KO) mice, and Men1 null mouse embryonic fibroblast (MEF) cell lines.
Examples are discussed for each category, and 1 example of each category is named here: 1) total ablation of the entire tissue with effort to replace ablated functions (for example, in C-cell neoplasia of multiple endocrine neoplasia type 2); 2) subtotal ablation with increased likelihood of persistent disease or recurrent disease (for example, in the parathyroid tumors of MEN1); or 3) no ablation of tissue with or without the use of pharmacotherapy (for example, with blockers for secretion of stomach acid in gastrinomas of MEN1).
Menin plays some physiological and pathological roles related to transforming growth factor-beta (TGF-β) signaling pathway in the parathyroid, and it is implicated in the tumorigenesis of parathyroid tumors.
We then examined expression of menin, caspase 8 and cyclin-dependent kinase inhibitors p27(Kip1) and p15(Ink4b) by Western blotting in human parathyroid tumors surgically resected from patients with MEN1 and those with non-hereditary primary hyperparathyroidism.
This observation correlates with the almost universal occurrence of parathyroid tumors accompanying the inactivation of menin in multiple endocrine neoplasia Type 1 (MEN1) syndrome and the high rate of somatic menin gene mutations seen in sporadic parathyroid adenomas.
We have identified a germ-line nonsense mutation in the human CDKN1B gene in a MEN1 mutation-negative patient presenting with pituitary and parathyroid tumors.
Cluster 2, characterized by HRPT2 mutations, was the most striking, suggesting that parathyroid tumors with somatic HRPT2 mutation or tumors developing on a background of germ-line HRPT2 mutation follow pathways distinct from those involved in mutant MEN 1-related parathyroid tumors.
Promoter hypermethylation of RIZ1 was detected in 36% of the parathyroid tumors and was related to LOH at the RIZ1 locus (P=.01), and absence of somatic mutation of the MEN1 gene (P=.044).
Here, we show that loss of Men1 gene function in the parathyroid glands of mice results in histological changes consistent with parathyroid neoplasia as well as systemic hypercalcemia.
Using microsatellite analysis for LOH at 11q13 and DNA sequencing of the coding exons, the MEN1 gene was studied in 38 parathyroid tumors of patients with sporadic PHPT.
Interest has focused on Smad3 as a candidate endocrine tumor suppressor gene because 1) it is localized to 15q and 2) it encodes a TGF beta signaling molecule that has been identified as a binding partner of the multiple endocrine neoplasm type 1 gene product menin, itself involved in enteropancreatic and parathyroid neoplasia.
The molecular genetic techniques of comparative genomic hybridization (CGH), loss of heterozygosity (LOH), and MEN1 mutation analysis were performed on a series of five patients with multiglandular PHPT, each of which had two parathyroid tumors removed.
Our data indicated that the majority of lithium-associated parathyroid tumors do not contain gross chromosomal alterations and suggest that in most cases the tumorigenic pathway is independent of MEN1 and genes at 1p34.3-pter and 1q21-q32.
These observations indicate that somatic inactivation of the MEN1 gene contributes to the pathogenesis of uremia-associated parathyroid tumors, but its role in this disease appears to be very limited.
Germ-line MEN1 gene analysis can distinguish heritable from nonheritable parathyroid tumors, and MEN1 gene evaluation of patients with apparently sporadic parathyroid tumor is recommended before parathyroid surgery.
Occasionally, the MEN1 gene mutation sites in sporadic parathyroid tumors are identical to those reported in tumors from patients with familial or sporadic MEN 1.