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

Abstract

Objectives: Investigation of small numbers of parathyroid tumours by X-chromosome inactivation analysis suggests that the majority of them are monoclonal lesions most likely caused by a somatic mutation. Somatic mutations in the MEN1 gene located on chromosome 11q13 have recently been identi®ed in 12±17% of solitary parathyroid tumours in patients with sporadic primary hyperparathyroidism, 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 parathyroid neoplasias we investigated 33 parathyroid tumours of patients with primary hyperparathyroidism for clonality and mutations in the MEN1 gene. Methods: X-chromosome inactivation analysis was used to assess the clonal status of the tumours, direct sequencing of the complete coding region was applied 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 androgen receptor on the X-chromosome and could be tested for inactivation pattern. Nineteen of twenty-six (73%) solitary adenomas were monoclonal. Somatic mutations in the MEN1 gene were identi®ed in nine cases. Six of them were found in the relatively large second exon of the MEN1 gene (A49D, 193del36, 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 monoclonal. In 26% of the monoclonal tumours a somatic MEN1 gene mutation has been identifed. However, for 74% of monoclonal tumours of the parathyroids the underlying genetic defects are still not known.

Chromosome 11 genomic changes in parathyroid adenoma and hyperplasia: Array CGH, FISH, and tissue microarrays

“…This par- ticular genomic change appears to have a prominent effect on the overall results of gene expression profiling of parathyroid tumors and was responsible for what we previously referred to as Type 1 and 2 parathyroid adenomas by expression analysis (Morrison et al, 2004). That we found this change in just slightly less than one-half of parathyroid adenomas is supported by prior LOH studies of the 11q13 locus or sequencing of the MEN1 gene which identified similar changes in 25 to 50% of parathyroid adenomas (Heppner et al, 1997;Carling et al, 1998;Farnebo et al, 1998;Karges et al, 2000;Miedlich et al, 2000;Uchino et al, 2000;Cetani et al, 2002;Correa et al, 2002;Tanaka et al, 2002). We have shown that loss of chromosome 11 is to a large part uniquely associated with deletion of the MEN1 locus, as other chromosome 11 genomic changes (11q23 deletion, CCND1 translocation) did not show such an association.…”

“…Genetic events involving the MEN1 gene are relatively well described in the context of familial hyperparathyroidism (MEN1), and are represented by a diverse set of mutations without specific genotypic phenotypic correlations. Loss of heterozygosity (LOH) of the MEN1 locus is a frequent event in sporadic parathyroid adenomas (Heppner et al, 1997;Carling et al, 1998;Farnebo et al, 1998;Karges et al, 2000;Miedlich et al, 2000;Uchino et al, 2000;Cetani et al, 2002;Correa et al, 2002;Tanaka et al, 2002). In addition to changes involving MEN1 and CCND1 at 11q13, other groups have shown evidence of a possible important tumor suppressor gene in parathyroid neoplasia at 11q23 (Hemmer et al, 2001;Pourani et al, 2002).…”

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

“…MEN1 tumour suppressor gene, which was identified in 1997 (15,16), encompasses ten exons that encode a 610 amino acid protein referred to as menin (17,18). Using polymorphic markers, loss of MEN1 locus was observed in 25-40% of sporadic parathyroid tumours, and an accompanying inactivating mutation was detected in about 50% of these tumours (19,20,21).…”

Molecular genetics in primary hyperparathyroidism: the role of genetic tests in differential diagnosis, disease prevention strategy, and therapeutic planning. A 2017 update

“…Two main genes have been associated to parathyroid adenomas in sporadic PHPT: oncosuppressor MEN1 and cyclin D1 gene (CCND1, OMIM gene 168461), both located in chromosome 11. Homozygous loss of MEN1 locus (caused by two distinct inactivating events at parathyroid somatic level) has been observed in 25-40% of sporadic parathyroid tumours (28,29) and it represents the most common genetic somatic alteration in sporadic PHPT. Pericentromeric inversions of chromosome 11, involving the PTH promoter and the CCND1 gene have been found in 8% of parathyroid adenomas (30).…”