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

Abstract

ObjectivePrimary 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 methodsWe 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. TheMEN1,RETandCDKN1Bmolecular study was carried out in the germline DNA by PCR/SSCP and direct sequencing. Parathyroid tumours were further analysed by the same methods forMEN1,CDKN1BandCTNNB1genetic alterations. The multiplex ligation-dependent probe amplification technique enabled the evaluation ofMEN1gene deletions. Protein expression for menin, cyclin D1, parafibromin, p27Kip1, β-catenin and Ki-67 was conducted by immunohistochemistry.ResultsThe study of parathyroid tumours detected two somaticMEN1mutations (c.249_252delGTCT and c.115_163del49bp) and revealed the presence ofMEN1intragenic deletions in 54% (13/24) of the tumours. InRETandCDKN1Bgenes only previously described, non-pathogenic variants were found. Cyclin D1 protein was overexpressed in 13% (3/24) of tumours.ConclusionsThese results suggest thatMEN1alterations, remarkably intragenic deletions, may represent the most prevalent genetic alteration in sporadic parathyroid tumours.