MEN1 intragenic deletions may represent the most prevalent somatic event in sporadic primary hyperparathyroidism

Abstract

Objective: Primary hyperparathyroidism (pHPT) is characterised by an inappropriate over production of parathyroid hormone and it is the most frequent pathological condition of the parathyroid glands. A minority of the cases belong to familial forms, but most of them are sporadic. The genetic alterations underlying the sporadic forms of pHPT remain poorly understood. The main goal of our study is to perform the molecular characterisation of a series of sporadic pHPT cases. Design and methods: We have studied matched blood and tumour from 24 patients with pHPT, who went to a medical appointment in Hospital Pedro Hispano. Informed consent was obtained from all individuals. The MEN1, RET and CDKN1B molecular study was carried out in the germline DNA by PCR/SSCP and direct sequencing. Parathyroid tumours were further analysed by the same methods for MEN1, CDKN1B and CTNNB1 genetic alterations. The multiplex ligation-dependent probe amplification technique enabled the evaluation of MEN1 gene deletions. Protein expression for menin, cyclin D1, parafibromin, p27Kip1 , b-catenin and Ki-67 was conducted by immunohistochemistry. Results: The study of parathyroid tumours detected two somatic MEN1 mutations (c.249_252delGTCT and c.115_163del49bp) and revealed the presence of MEN1 intragenic deletions in 54% (13/24) of the tumours. In RET and CDKN1B genes only previously described, non-pathogenic variants were found. Cyclin D1 protein was overexpressed in 13% (3/24) of tumours. Conclusions: These results suggest that MEN1 alterations, remarkably intragenic deletions, may represent the most prevalent genetic alteration in sporadic parathyroid tumours.

Genomics and Epigenomics in Parathyroid Neoplasia: from Bench to Surgical Pathology Practice

“…Expression studies regarding menin and associations to underlying MEN1 mutational status in parathyroid tumors have been promising, as menin immunohistochemistry seem to exhibit high sensitivity to detect underlying MEN1 mutations and/or gene deletions [132,133]. Even so, the interpretation of menin immunohistochemistry is not straightforward, and the lack of comprehensive studies on the subject makes menin immunohistochemistry inappropriate for clinical routine screening purposes.…”

Evidence of a Functional Estrogen Receptor in Parathyroid Adenomas

“…(Yokoyama et al, 2005) A recent study reported MEN1 intragenic deletions in 13/24 parathyroid adenomas using FFPE material, but this alteration remains to be reproduced. (Alvelos et al, 2013) Multiple endocrine neoplasia type 2 (MEN 2)…”

The Oncosuppressors MEN1 and CDC73 Are Involved in lncRNA Deregulation in Human Parathyroid Tumors

“…4B). The importance of chromosome 11 in parathyroid pathogenesis is well established, because the MEN1 gene maps at 11q13.1, ( 30 ) and MEN1 ‐inactivating mutations through LOH at 11q are the most frequent finding in sporadic adenomas. ( 28 ) In keeping with this, PAds with chr11 normal haplotype showed higher MEN1 mRNA expression than adenomas with chr11‐LOH ( p = .03; Fig.…”