Frequency of somatic MEN1 gene mutations in monoclonal parathyroid tumoursof patients with primary hyperparathyroidism

Objectives: Investigation of small numbers of parathyroid tumours by X-chro mosome inactivation analysis suggests that the majority of them are monoclo nal lesions most likely caused by a somatic mutation. Somatic mutations in the MEN1 gene located on chromosome 11q13 have recently been identified in 12-17% of solitary parathyroid tumours in patients with sporadic primary hy perparathyroidism, and they may be the precipitating genetic defect leading to monoclonal cell proliferation in these tumours. Design: To determine the prevalence of MEN1 gene mutations in monoclonal pa rathyroid neoplasias we investigated 33 parathyroid tumours of patients wit h primary hyperparathyroidism for clonality and mutations in the MEN1 gene. Methods: X-chromosome inactivation analysis was used to assess the clonal s tatus of the tumours, direct sequencing of the complete coding region was a pplied to identify mutations in the MEN1 gene. Results: Twenty-eight female patients (26 patients with solitary adenoma, 2 patients with hyperplasia) were informative for the polymorphism of the an drogen receptor on the X-chromosome and could be tested for inactivation pa ttern. Nineteen of twenty-six (73%) solitary adenomas were monoclonal. Soma tic mutations in the MEN1 gene were identified in nine cases. Six of them w ere found in the relatively large second exon of the MEN1 gene (A49D, 193de 136, 402delC, 482del22, 547delT, W126X). One was found in exon 5 (904del9). one in exon 7 (Y327X) and one in exon 9 (R415X). Of the monoclonal tumours , 5 out of 19 (26%) harboured a somatic MEN1 gene mutation. Conclusions: In summary, 73% of the solitary parathyroid adenomas were mono clonal. In 26% of the monoclonal tumours a somatic MEN1 gene mutation has b een identifed. However, for 74% of monoclonal tumours of the parathyroids t he underlying genetic defects are still not known.